Finals Reviewer – LE 2 PHYSIOLOGY

March 11, 2018 LE 2

OUTLINE HEMATOPOIESIS
• production and maturation from a single type of cell called the
pluripotent hemapoetic stem cell (PHSC) from the bone
2.01 Red Blood Cells
marrow
2.02 Hemostasis
2.03 White Blood Cells
2.04 Pediatric Hematology A. Long Term Hematopoietic Stem Cell (LT-HSC)
2.05 Introduction to Immunology • Found in the bone marrow
2.06 Respiratory Physiology I • Has the capability to divide, self-renew and differentiate
2.07 Respiratory Physiology II • Differentiates into ST-HSC
2.08 Regulation of Respiration
2.09 Pediatric Respiratory Physiology B. Short Term Hematopoietic Stem Cell (ST-HSC)
• Committed into the different cellular elements of blood
• gives rise to Burst-forming units (BFUs) and/or
2.01 Red Blood Cells Colony-forming units (CFUs)
• BFUs and CFUs will form erythrocytes, platelets,
BLOOD PHYSIOLOGY eosinophils, basophils, neutrophils, monocytes, B-or T-
• A complex fluid consisting of plasma and formed element lymphocytes, NK cells
such as RBCs, WBCs, and platelets. Also being categorized
as a connective tissue. Growth and differentiation inducer (cytokines)
• ILK 3 – growth inducer all types of ST-HSC
Table 1. Blood characteristics. • ILK 5 –for eosinophils
Male: 4 – 6 L • Thrombopoietin – platelets
Volume • Erythropoietin – red blood cells
Female: 4.5 – 5.5 L
Whole blood: 6 – 8% • GM-CSF – for proliferation of Common Myeloid
% body weight Progenitor (CFUGEMM) which produces the CFUs for
Plasma: 5%
Specific Gravity Whole blood: 1.050 neutrophils, eosinophils, and monocytes
(Compared to H2O) Plasma: 1.025
Viscosity 3.5 – 5.5 x H2O ERYTHROCYTE

Note: viscosity is affected by:

o Hematocrit
o Fibrinogen
o Radios of blood vessel
o Velocity of blood flow
o Temperature

A. Functions

• Transport: of gases, nutrient, hormones, enzymes,

electrolytes, waste materials and heat
• Defense: (WBC)
• Repair: (hemostasis)
• Regulation: by mean of acid - base balance, maintenance of
body temperature and body fluid Figure 1. Characteristics of erythrocytes.
B. Main Components A. Functions
• Transport of gases which are bound to hemoglobin
1. Plasma (55%) – solution off electrolytes, proteins, carbs, and • Carbonic anhydrase for CO2 transport - Acid base
lipids. buffer
• Serum: plasma WITHOUT coagulation factors – H2O
(91.5%), proteins (7.5%), solutes/waste (1%) B. Main Component
• Plasma Proteins • Hemoglobin – bright red color of blood (oxygenated)
o Albumin: major plasma protein; primarily to maintain • 2,3-bisphosphoglycerate (BPG) – reduced
oncotic pressure; also acts as transporter hemoglobin affinity to oxygen
o Globulin: alpha (α), beta (β), gamma (γ)
• Glutathione – protects RBC from oxidant damage
o Fibrinogen: synthesized only by the liver; converted
• Carbonic anhydrase – catalyzes formation of carbonic
into fibrin (for hemostasis)
acid
2. Formed elements (45%)
C. Erythropoiesis – Formation of RBCs from CFUs
• composed of erythrocytes, leukocytes, and platelets
• Proerythroblast – first cell identified in RBC lineage
• Hematocrit – total percentage of RBC in blood
• Erythroblasts/Normoblast
o Male = 47% (+/- 5%)
o Female = 42% (+/- 5%)

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 • Reticulocyte
o contains basophilic elements
o from bone marrow, goes to circulation via
diapedesis
o basophilic elements disappear for 1-2 days and
becomes mature RBC
o still normally found at blood 2%
• Mature RBC
Note: no. of reticulocyte ∝ rate of RBC production
D. Factors Affecting RBC Production
• Iron
o needed in reticulocyte and erythrocyte formation
o binds with protoporphyrin IX
• Vitamin B12 and Folic acid
o both needed for final RBC DNA synthesis
• Erythropoietin (EPO)
o increases erythropoiesis
o stimulate proliferation and differentiation of
committed cells
• Hypoxia (â oxygen)
o triggers Hypoxia-Inducible Factor 1 (HIF-1)
o promotes erythropoietin production
• Intrinsic factor
o secreted by the parietal cells in stomach
o needed for absorption of Vitamin B12 in the ileum
HEMOGLOBIN (Hgb)
• Two ∝-chains (2) and two β- chains (2) structure; contains
ferrous form of iron (Fe2+) – Heme
RBC MEMBRANE TRANSPORTERS
• CL- HCO3- Exchanger AE1 (aka BAND 3)
o for carrying of carbon dioxide
o most abundant in RBC
• Aquaporin
o contributes to carbon dioxide permeability of RBC
o 2nd most abundant in RBC
• Glycophorin
o transports glucose via facilitated diffusion
o cytoskeleton that maintains RBC shape is attached to the
cell membrane by glycophorin and AE1
RBC DEGRADATION
A. RBC Lifespan
• Lifespan of RBC = 120 days
• Death and Release of RBC contents - Hemolysis
• Hemoglobin components of blood are recycled
o Heme - converted à biliverdin à bilirubin à then
secreted in bile from liver
o Iron - transported in the blood by the protein
Transferrin then stored by the protein Ferritin in
the liver
o Membrane proteins and globin proteins are broken
down into amino acids
B. Iron Metabolism
• Food Iron - absorbed by intestine
o Heme iron: readily absorbed via Heme Transporter
o Non-Heme iron (Fe3+): converted to Fe2+in
duodenum; absorbed via DMT1 (Divalent Metal
Iron Transporter)
• Fe2+ move out of intestine via Ferroportin 1
• transported through the blood (by attaching to
Transferrin) and will go to liver (for storage) or bone
marrow (for erythropoiesis

BLOOD TYPES

A. ABO Blood System

Figure 2. Hemoglobin synthesis and maturation. • Agglutinogens – Antigen on the surface of RBC
• Agglutinins – Antibody on Plasma/ Serum
A. Hemoglobin Synthesis (During Proerythroblasts to
• Four Major blood types:
Reticulocytes)
o Type A, B, AB, O
• 2 succinyl coA + 2 glycine - 4 pyrrole
• 4 pyrroles - protoporphyrin IX Table 3. Blood type.
• protoporphyrin IX + Fe2+ - heme Blood
• heme + polypeptide - hemoglobin chain (alpha or beta) Genotypes Agglutinogens Agglutinins Prevalence
types
• 2 alpha chains + 2 beta chains - Hb A Anti-A
OO O -- 44 – 46%
Anti-B
B. Hemoglobin Abnormalities OA or AA A A Anti-B 22 – 23%
• Qualitative or structural – incorrect DNA code OB or BB B B Anti-A 24 – 25%
(hemoglobinopathy) AB AB A and B -- 4 – 6%
• Quantitative – production of globin chains is reduced or
absent (thalassemia) B. Blood Typing
• Hereditary persistence of Fetal hemoglobin (HPHF) – • Blood sample antigens is mixed with various antibodies
failure of gamma globin to switch to beta globin chain (solutions: anti-A: blue, anti-B: yellow)
• agglutination indicates the presence of the
Table 2. Type based on transport molecules. corresponding antigen
Hemoglobin Type Molecule
Oxyhemoglobin Oxygen C. Rh Incompatibility
Deoxyhemoglobin No oxygen • Rh (+) : presence of Rh antigen
Carbaminohemoglobin CO2 • Rh (-) : absence of Rh antigen
Methemoglobin Fe3+
Carboxyhemoglobin CO Erythroblastosis Fetalis – Hemolytic disease of the newborn
Sulfhemoglobin Sulfur (Trans 2.01, pg. 8)
• Prevention: Mother is given anti-Rh D immunoglobulins
on 28th week of gestation of first pregnancy and right
after delivery

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 CLINICAL CORRELATIONS B. ACTIVATION
• Binding ® conformational change ® granule content
A. Anemia release (alpha and dense core granules) ® recruitment
• insufficient number of RBC of more platelets ® ­ aggregation
• Decreased/ Abnormal Hemoglobin content • Conformational change in GpIIb/IIIa
o Iron deficiency o Oval to finger-like pseudopodia shape
o Vitamin B12 (Pernicious anemia) • Platelet activators:
o Folic acid o Collagen – from damaged endothelium
o Abnormal Amino Acid chain o ADP – from damaged RBCs and activated platelets
• Parameters: o TXA, Platelet Factor 3 – from activated platelets
o Normocytic, Normochromic o Thrombin – circulating in plasma
= Acute hemorrhage, hemolysis
o Microcytic, Hypochromic
= Iron deficiency
Notes:
o Macrocytic, Normochromic
• Functions of Thrombin:
= Vitamin B12 or Folic acid deficiency
o Activation of platelets
o Activation of clotting factors V, VIII, XIII
B. Polycythemia
o Converts Fibrinogen à Fibrin
• increase in RBC count
o also a Vitamin-K dependent clotting factor
• Classification: o Inhibition of Thrombin activity à increase
o Polycythemia Vera – high RBC count BLEEDING TIME, CLOTTING TIME and
o Inapparent Polycythemia Vera – increase in
PROTHROMBIN
plasma volume
o Secondary Polycythemia – similar blood volume to
that of the normal; high RBC count
C. AGGREGATION
o Relative Polycythemia – low plasma volume; high
• Recruitment: ADP, Serotonin, TXA activates additional
RBC count
platelets
• Platelet plug: Fribrinogen binds with GpIIb/IIIa
2.02 Hemostasis
• Balance between coagulation and anticoagulation Notes:
1. Vascular Constriction • Factors affecting Platelet Aggregation
2. Platelet Plug formation Endothelial cells secrete:
3. Formation of Blood Clot o Prostacyclin: inhibits platelet aggregation
4. Clot Retraction and Fibrinolysis o ADPase: degrades ADP
o Thrombomodulin: binds with thrombin; less
VASCULAR CONSTRICTION activity
Blood vessel cut/ ruptured ® smooth muscle contraction,
leading to the following:
• Local Myogenic Spasm CLINICAL APPLICATION
• Local Autocrine Factors
o Serotonin; Thromboxane A2, Endothelin Intake of Aspirin
• Neural Reflexes • Aspirin – COX inhibitor, prevents aggregation
o Pain nerve impulses • COX – produces Thromboxane A2, important for platelet
aggregation
Note: The more severely a vessel is traumatized, the greater the • Low dose of Aspirin inhibits Thromboxane A2 synthesis
degree of vascular spasm. • Patients on Aspiring will most likely have prolonged bleeding
time and unaffected PT, PTT, & platelet count
PLATELET PLUG FORMATION (PRIMARY HEMOSTASIS)
PLATELETS (THROMBOCYTES) BLOOD COAGULATION (SECONDARY HEMOSTASIS)
• Bud off from megakaryocytes • Coagulation Cascade ® Prothrombin activator ®
• Size: 2-4μm Prothrombin ® Thrombin ® Fibrinogen ® Fibrin Mesh Clot
• Lifespan: 8-12 days (stable clot)
• Normal levels: 150,000-450,000 cells/μL • Coagulation cascade involves an Extrinsic and Intrinsic
• Has 2 special organelles: Pathway
o α granules – vWF, platelet fibrinogen, F5 • Procoagulants – clot formers
o dense-core granules – ATP, ADP, serotonin, Ca2+ o Thrombus: too much clot formers without thinner;
can cause heart attack
THROMBOPOEITIN o Anticoagulant: blood thinners
• Produces platelet
o 2/3 of total platelets ® blood stream
Notes:
o 1/3 of total platelets ® stored in spleen
• Platelet Plug Formation: TEMPORARY CLOT
• Blood Coagulation: PERMANENT/ FINAL CLOT
PLATELET PLUG FORMATION PROCESS

A. ADHESION
• Binding of platelets self or other components
• Platelet receptors: GpIb/Ia (Gp1b/IX)
o No receptor = no adhesion
• Ligands: Von Willebrand Factor (vWF), collagen,
laminin, fibronectin

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 INTRINSIC PATHWAY

Figure 3. Summary of blood coagulation.

CLOTTING FACTORS

Table 4. Clotting factors in platelet coagulation.

CLOTTING
SYNONYMS
FACTOR
Factor I Fibrinogen
Factor II Prothrombin
Factor III Tissue Factor
Factor IV Calcium
Factor V Proaccelerin, Labile Factor
Serum Prothrombin Conversion Figure 5. Intrinsic pathway.
Factor VII Accelerator (SPCA)
Proconvertin; stable factor • Dependent on internal stimuli
Antihemophilic factor (AHF), • Clotting factors come in contact with the endothelial lining
Factor VIII Antihemophilic globulin (AHG); (collagen) ® cascade of activation ® coagulation; hence
Antihemophilic factor-A called Surface Contact Activation
plasma thromboplastin component (PTC); • Slower pathway; Measured by Partial Thromboplastin Time
Factor IX Christmas factor (PTT) or Activated Partial Thromboplastin Time (APTT)
Antihemophilic factor-B
Factor X Stuart Factor; Stuart-Power Factor
Plasma Thromboplastin Antecedent (PTA); Notes:
Factor XI
AHF-C • Clotting Factors in Intrinsic Pathway:
Factor XII Hageman Factor o Factors 8, 9, 11, 12
Factor XIII Fibrin-Stabilizing factor o HMWK
Prekallikrein Fletcher Factor o Pre-Kallikrein
HMWK High Molecular Weight Kininogen
Ka Kallikrein
COMMON PATHWAY
EXTRINSIC PATHWAY • Connects intrinsic and extrinsic pathways
• Measured by PT and PTT

Figure 4. Extrinsic pathway.

• Dependent on external stimuli or damage

Figure 6. Summary of clotting factor cascade.
• Tissue is found outside the blood vessel, thus the
extrinsic pathway is called Tissue Factor Activation
• Faster pathway; measured by Prothrombin Time (PT)

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 2. Hemophilia
Notes: • Excessive bleeding; X-linked disorder
• Clotting Factors in Common Pathway: • Prolonged PTT, unaffected PT, BT and platelet count
o Factors 1, 2, 5, 10, 13 • Abnormality in specific clotting factors
• Calcium is very important! o Hemophilia A: Factor VIII
• Clotting factors made by liver and need Vitamin K for o Hemophilia B: Factor IX
synthesis • Remedy: replacement of clotting Factors
• Both pathways occur simultaneously
• Vitamin K dependent factors: Factor X, IX, XII, II B. Vitamin K Deficiency
• Vitamin K is synthesized by intestinal bacteria
TO REMEMBER: 1972 = 10, 9, 7, 2 and activates Factor X, IX, VII, and II
• Deficiency results from:
o Poor absorption of fats
CLOT RETRACTION o Lack of bacterial flora (e.g. neonates)
• Platelets: release coagulation factors o Liver damage
• Dependent on the following proteins: Thrombosthenin, Actin, o Remedy: Vitamin K analogue
Myosin
• Accelerated by Thrombin and Calcium C. Disseminated Intravascular Coagulation (DIC)
• Prolonged clot retraction ® Platelet dysfunction • ↑ consumption of platelets and clotting factors
• Antecedent events: complicated labor, sepsis,
ANTICOAGULANTS cancer, pancreatitis, surgery, liver disease
• Prevent coagulation ® bleeding does not stop • Laboratory results:
• Types of Anticoagulants: o Prolonged BT, CT, PT, PT
o Endothelial Surface Factors o Low platelet count
§ Thrombomodulin binds thrombin ® no clot
activation FIBRINOLYSIS
o Protein C • Process of breaking down product of coagulation, a fibrin clot
§ Inactivates Factors V (common pathway) and VIII • Plasmin: active component of Plasminogen
(intrinsic pathway) o Main protagonist in fibrinolysis
o Antithrombin III (aka Antithrombin-heparin cofactor) o Cleaves stable fibrin into fibrin breakdown products
§ Inactivates thrombin • Tissue Plasminogen Activator (tPA)
o Heparin o Released by activated endothelial cells
§ Little or no anticoagulant properties by itself o Responsible in activating Plasminogen
§ Enhances the effect of antithrombin
§ Complex of heparin + antithrombin III removes
Factors IX, X, XI, XII Notes:
o Tissue Factor Pathway Inhibitor • Protein S (+ activated Protein C) degrades activated
§ Inhibits Factor Xa, TF + Factor VII Complex factors V and VII.
(extrinsic pathway) • Deficiency of Protein S will result in EXCESSIVE
CLOTTING
ANTICOAGULANTS: MEDICATIONS
• PT is used to monitor the activity of Warfarin because it
measures the activity of Vitamin-K dependent clotting
A. Heparin factors.
o For Deep Vein Thrombosis (DVT)
o Action: 1.5-4 hours
o Affects Factors II, IX, X, XI, and XII
LABORATORY TESTS
o Monitored with PTT
Table 5. Laboratory test used in Platelet Disorders.
B. Warfarin
TEST NORMAL VALUE
o Oral route ® slower action
Platelet Quality 150,000 – 450,000/μl
o Action: 1-3 days
o Affects Factors II, VII, IX, X (1972), Protein S, and Platelet Quantity 1 – 6 minutes
Protein C Clotting Factors 6 – 10 minutes
o Monitored with PT Extrinsic Pathway 12 – 15 minutes
o Effect can be reversed by Vitamin K
Partial
C. Chelating Agents (Oxalate, EDTA) thromboplastin Intrinsic Pathway 25 – 30 seconds
o Bind with Ca2+ ® ¯ Ca2+ ® ¯ clotting factors Time (PTT)
PT and PTT Common Pathway -
CLINICAL CORRELATION
2.03 White Blood Cells
A. Hereditary Bleeding Disorders:
OVERVIEW OF WHITE BLOOD CELLS
1. von Willebrand Disease (quality problem)
• Function of vWF: WHITE BLOOD CELLS
o Enhances platelet adhesion and aggregation • Also known as leukocytes
o Stabilizes factor VIII • Cells of the immune system responsible for protecting the
• A disorder in primary hemostasis body against infectious disease and foreign invader
• Can also affect secondary hemostasis by: • Derived from multipotent hematopoietic stem cells and
o vWF stabilizes clotting Factor VIII originates from the bone marrow
o Without vWF, activity of factor VIII is affected
o Affects intrinsic pathway because of factor VIII

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 • Found throughout the body – including the blood and Eosinophils
lymphatic system • Play important role in combating parasitic infections such
• Normal WBC count in adults: 4.3–10.8 × 109/L (4,300 to as helminths
10,800 cells per μL of blood) • Involved in allergic diseases such as asthma and in various
• Leukocytes (along with platelets) constitutes around <1% of respiratory and GI diseases
blood, while plasma constitutes of around 55%, and
erythrocytes constitutes around 45% of blood Table 8. Clinical Cases of Eosinopenia and Eosinophilia. (AEC –
Absolute Eosinophil Count)
• Neutrophils EOSINOPENIA EOSINOPHILIA
o Most abundant type of leukocyte: 40 - 70% of (AEC < 50 cells/uL) (AEC > 500 cells/uL)
leukocytes in circulation o Severe Sepsis o Allergies
o Approx. 90% of the neutrophil pool is in the bone o Chemotherapy o asthma
marrow, while 2 - 3% are in circulation. The rest are o Aplastic Anemia o Hay Fever
in the tissues o Certain Reaction to Drugs o Parasitism**
• Eosinophils o Myelodysplastic Syndrome o Hypereosinophilic Neoplasm
o 0-6% of WBCs in circulation; approximately 3% of **been asked during LE
nucleated bone marrow cells
• Basophils AGRANULAR
o Least abundant of the white blood cells: • Monocyte
o 0-2% of circulating leukocytes o Phagocytic function
o <1% in bone marrow
• Monocytes Table 9. Clinical Cases of Monocytopenia and Monocytosis.
o Relatively smaller in number, 4-8% of circulating MONOCYTOPENIA MONOCYTOSIS
WBC (AMC < 100 cells/uL) (AMC > 800 cells/uL)
• Lymphocytes o Hairy Cell Leukemia o Chronic Infections /
o Make up between 20-50% of circulating leukocytes o Myelodysplastic Syndrome Inflammations
o Can be Granular/ Agranular o Aplastic Anemia (e.g. TB, syphilis, subacute
o Certain Reaction to Drugs bacterial endocarditis)
GRANULAR o Collagen Vascular Disease
o Monocytic Leukemia
Neutrophils
• Phagocytose and destroy foreign material and
microorganisms Immune Cells derived from Monocyte
• Secretion of various cytokines, transcobalamin I or R binder • Plasma Cell: produce antibodies
protein (necessary for absorption of vitamin B12) • Lymphocytes: specific immune response
• B cell: upon contact with antigen, they become memory cells
Table 6. Clinical Cases of Neutropenia and Neutrophilia or effector cells
NEUTORPENIA (2,000 cells/ μL) NEUTROPHILIA • T cell: when in contact with an antigen, they become either
o Severe sepsis 3 most common: memory cells or effector cells
o Chemotherapy o Acute bacterial infection • NK cell: function as part of innate immunity and are capable
o Aplastic anemia o Acute inflammation of killing certain tumor cells and virus-infected cells
o Autoimmune disease o Tissue necrosis
o Reaction to drugs (most Table 10. Clinical Cases of Lymphopenia and Lymphocytosis
common) o Pregnancy LYMPHOPENIA LYMPHOCYTOSIS
o Myelodysplastic syndrome o Chronic leukemia (ALC < 1000 cells/uL) (ALC > 5000 cells/uL)
o Stress (due to effect of Immunodeficiency State
Catecholamines on production Acute Viral Infection
(HIV Infection)
and mobilization of
Other Bacterial Infection
Neutrophils) Autoimmune Disease
(Pertussis, TB)
o Strenuous exercise
o Recent surgeries Chemotherapy Lymphocytic Leukemia
o Smoking (decreases apoptotic Bone Marrow Problem Lymphoma
effects of neutrophils)
Mast Cell*
Basophils A. not considered leukocytes, but as tissue effector cells of
• as initiators and mediators of the allergic reaction through allergic responses and inflammatory reactions
the release of preformed cytokines and leukotrienes B. anti-inflammatory and immunosuppressive functions

Table 7. Clinical Cases of Basopenia and Basophilia (ABC – LEUKOPOIESIS

Absolute Basophilic Count)
BASOPENIA
o Severe Sepsis
o Chemotherapy
o Aplastic Anemia
o Certain Reaction to Drugs
o Myelodysplastic Syndrome
BASOPHILIA A. Production of different subtypes if leukocytes are stimulated
by chemicals called Cytokines (autocrine regulators secreted
(ABC > 100 cells/uL)
o Rare Allergic Reactions by various immune cells)
o Inflammation • Pluripotent hematopoietic stem cell
o Leukemia 1. Initiates the production of white blood cells
o Polycythemia Vera 2. Progress into either Common Myeloid progenitor or
Common Lymphoid progenitor

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 • Common Myeloid progenitor: responsible for
producing granular leukocytes and monocyte
o The progression is Myeloblast and form into
either:
§ Eosinophilic Myeloblast à forming
Eosinophil
§ Basophilic Myeloblast à Basophil
§ Neutrophilic Myeloblast à Neutrophil
§ Monoblast - Monocyte à Macrophage
• Common Lymphoid progenitor: is responsible for
producing B and T lymphocytes and NK cells
o Forming of Lymphoblast into prolymphocyte,
further progresses into:
§ NK cells
§ T cells
§ B cells
• Cytokines known as MULTIPOTENT GROWTH FACTOR-1,
INTERLEUKIN-1, and INTERLEUKIN-3 have general effects
in stimulating development of different types of white blood
cells
• COLONY-FORMING UNIT-GRANULOCYTES
MACROPHAGE stimulates development of neutrophils and
monocytes
PHAGOCYTOSIS
• Selective process of cellular ingestion and digestion of an
offending agent/ pathogen
• Must be selective of the material that is phagocytized; otherwise,
normal cells and structures might be ingested (Guyton)
Important Function of Neutrophils and Macrophages
• 1 neutrophil can usually phagocytize 3-20 bacteria
• 1 macrophage is capable of phagocytizing as many as
100 bacteria, as well as much larger particles.
Factors that Increase the Likelihood of Phagocytosis
A. Roughness of surface
B. Absence of a protective protein coat
C. Presence of opsonins
Mechanism of Phagocytosis
STEP 1: RECOGNITION AND ATTACHMENT
• Bacteria release chemotactic factor to attract
polymorphonuclear leukocytes (PMN) or granulocytes
• On approaching a particle to be phagocytized, the phagocyte
attaches itself to the particle.
• Phagocytosis is efficiently promoted by opsonization of
bacteria or foreign particles with antibody and complement
o OPSONIZATION is the process coating of the
pathogen by complement fragments (C3b), antibodies,
and acute phase proteins
STEP 2: INGESTION
• Pseudopodia are extended around the pathogen and enclose
it within a phagosome (phagocytic vesicle)
o Phagosome: like a special vesicle for pathogen
• Phagosome is pulled toward the center of the cell by
polymerization of actin and myosin and by microtubules
STEP 3: KILLING AND DIGESTION
• Oxygen-independent
• Primary and secondary lysosomes (granules) fuse to the
phagosome and empty hydrolytic enzymes and other
bactericidal molecules
• One of lysosomal enzymes, myeloperoxidase, catalyzes the
reaction between H2O2 and chloride ions to form
hypochlorite, which is exceedingly bactericidal
• Oxygen-dependent
• Respiratory burst via the activation of NADPH
• H2O2 and hypochlorite are produced
*Remnants/ debris of the pathogen is excreted or recycled by the
phagocyte
INFLAMMATION
• Body’s response to noxious stimuli which may include any
physical or chemical invasion by pathogens
• An initial, complex, and localized response of vascularized
tissues to infections and tissue damage that bring cells and
molecules of host defense from the circulation to the sites
where they are needed to eliminate the offending agents.
(Rhoades; Ganong)
• It causes dramatic sensory changes in the surrounding
uninjured tissues through the release of multiple substances
during tissue injury. (Guyton)
• Causes include: infections, tissue necrosis, foreign bodies,
trauma, and immune responses
Cardinal Sign of Inflammation
• Rubor (Redness): Dilation of blood vessels causing
blood to flow more at the site of inflammation
• Calor (Heat): Warm sensation due to dilated blood
vessels (as body heat is controlled by blood circulation)
• Dolor (Pain): Nerve endings are impinged by the
swelling
• Tumor (Swelling): Extravasation of the cells and the
fluid into the tissues brought about by increased capillary
permeability
• Functio Laesa (Loss of Function): Loss of function due
to swelling and pain
Types of Inflammation
ACUTE INFLAMMATION
• Short duration (minutes-days)
1. Rapid onset
2. Mediators: Neutrophils (primary), eosinophils, antibodies
3. 3 main components:
o Increased blood flow to inflamed area;
o Structural changes in vessels allow migration of cells
and plasma protein;
o Emigration or transfer of WBCs to the site of injury
• Outcomes: Complete resolution, abscess formation, or
progression to chronic inflammation
CHRONIC INFLAMMATION
• Delayed response
• More specific than acute inflammation
• Failure to resolve inflammation
• Mediators: Lymphocytes (hallmark), and macrophages
• Outcomes: Proliferation of blood vessels (angiogenesis),
fibrosis, and necrosis
Cellular and Vascular Response During Inflammation
• Vasodilation to allow more blood flow through the vessel
• Structural change (vascular permeability) will allow
aggregation of several components such as: RBCs,
platelets, and WBCs to pass through
• With persistent increase in vessel diameter will
eventually lead to stasis of blood (slowing of blood flow)
• As blood stasis develops, leukocytes will marginate along
vascular surface and will begin emigration to the site of
injury
Leukocyte Adhesion Cascade
STEP 1: MARGINATION
• Cells marginate from the center of the blood flow to the
periphery to come in contact with the activated endothelium
• Capture/ tethering
o occurs after margination
o first contact of the leukocyte with the activated
endothelium
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STEP 2: ROLLING
• Selectins are upregulated on endothelial cells which bind to
2.04 Pediatric Hematology
glycoproteins on leukocytes. This interaction results to rolling
of leukocytes along the vessel wall. DEVELOPMENTAL HEMATOPOIESIS
• This would slow down the movement of leukocytes making it • Constant and marked growth characterizes all kinds of
closer to the endothelium hematopoiesis in embryo and fetus, due to this there is high
• P-selectin is the primary adhesion molecule for capture and demand by these cells.
initiation of rolling. • The interpretation of lab values will really depend on the age
o e.g. Hgb of 17g is normal for 1 day old, but polycythemic
STEP 3: ADHESION for a 21 y/o.
• Cellular adhesion molecules (CAMs) are upregulated on
endothelial cells while integrins are upregulated on A. Inducers of Mesoderm
leukocytes. • The following inducers regulate the onset of
• Binding of integrins to ICAM leads to the stable adherence of hematopoiesis:
the cells to the endothelial cells surface. a. Transforming Growth Factor β (TGF-β)
• Platelet-activating factor (PAF) also stimulates leukocyte- b. Fibroblast Growth Factor
endothelial cell adhesion. c. Bone Morphogenic Protein (BMP-4)

STEP 4: TRANSMIGRATION AND CHEMOTAXIS B. Differentiation of Cell Lines

• Leukocytes transmigrate across the endothelium of • Hematopoietic cells are derived from mesoderm.
postcapillary venules (diapedesis), and move towards • Starts with pluripotent stem cells (PSC) which are
chemical attractants (chemotaxis). uncommitted and capable of self-renewal.
• Diapedesis involves platelet-endothelial cell adhesion • Cytokines control the differentiation process,
(PECAM-1) which is expressed both on emigrating transforming PSC into colony-forming units (CFU):
leukocytes and endothelial cells. • Types:
a. CFU-GM: Granulocytes &Monocytes
CLINICAL CONSIDERATIONS b. CFU-Mega: Megakaryocytes & Platelets
• Leukocytosis c. CFU-E: Erythrocytes
o An increase in total WBC count
o Usually > 10,000 cells/Ul C. Intrauterine Development
• Leukopenia 1. Yolk Sac: 10th – 14th, ends by 10-12 weeks
o A decrease in total WBC count 2. Liver/Spleen: 6th – 2th week, ends in 2nd late semester
o Usually < 4000 cells/uL 3. Bone Marrow: mid-3rd trimester
• Severe Inflammatory Response Syndrome (SIRS)
ADULT HEMATOPOIESIS – in addition to the bone marrow (red)
o Has 2 or more of the following:
o Leukocytosis, leukopenia, or 10% Bands hematopoietic tissues are also found in flat bones.
o Fever (Pyrexia/Hyperthermia) or decreased temperature
RED BLOOD CELLS
(Hypothermia)
o Rapid respiration (Tachypnea) = >24 breaths/min • FUNCTIONS: for O2 Transport, Buffer System (acid-base),
o Increased heart rate (Tachycardia) = >90 beats/min Immunity (antibodies & complement)
• Sepsis
A. Fetal Characteristics of Developmental Erythropoiesis
o SIRS, and proven or suspected microbial etiology
• Constant growth observed in the fetus presents a
• Severe sepsis:
necessity to increase red cell mass which requires
o Sepsis, and >1 signs of organ dysfunction
extreme erythropoietic effort.
• Septic shock:
o Sepsis with hypotension • Needs a different system of O2 delivery since oxygen
tension is low and metabolic demands are high.
• Leukemoid Reaction (LR)
B. Erythropoiesis in Utero
o A secondary reversible significant increase in the number
of leukocytes in response to a stimulus (acute stressful • Erythroid Growth Factors controls erythropoiesis in
fetus.
events or infection)
o Produced by accessory cells: Macrophages,
o Total WBC counts greater than 50,000 cells/uL
Lymphocytes, and Stromal Cells.
§ this is the normal morphology of cells
o If cells have abnormal forms = leukemia • Erythropoietin (EPO) does not cross the placenta
o Source: Liver (primary), kidneys
• Leukocyte alkaline phosphatase (LAP) score may help
differentiate between LR and hematologic malignancy
C. Erythropoiesis After Birth
• Some causes – infection, hemolysis, necrosis, and effect of
cytokines; may lead to malignancy • Expansion of the lungs = improved O2 availability and
delivery = near cessation of RBC production both in term
• Leukemia
and preterm infants.
o “cancer of blood cells”
o uncontrolled production of abnormal WBCs in the blood • At Birth 55-65% is HbF¸ its production decreases
circulation thereafter
o general classifications: (1) origin: myeloid or lymphoid; (2)
D. Anatomic Sites
acute vs chronic
• Granulocytopenia
1. Mesoblastic (Extraembryonic/Yolk Sac - primary source of
o reduced numbers of granulocytes
RBC in 1st trimester)
o neutrophils, eosinophils, and basophils
• Agranulocytosis
PRIMITIVE ERYTHROBLASTS:
o complete absence of blood granulocytes
• Nucleated as they circulate
o often is used to indicate severe neutropenia
• High sensitivity to EPO = more rapid maturation
• Peripheral Blood Smear (PBS)
o may be included in the initial evaluation when there are • Large
abnormalities in the blood counts

8 of 22
YOLK SAC HEMATOPOIESIS:
• At 4 weeks gestation BLOOD VOLUME @ birth = weight (kg) x 85mL/kg
o Erythroid progenitors BLOOD VOLUME @ 1 month = weight (kg) x 73-77 (range) mL/kg
o Burst-forming units-erythroid (BFU-E) Early clamping – low blood volume; delayed clamping – high blood
o Later erythroid progenitors volume
o CFU-E
à Primitive erythroblasts and erythroid progenitors: enter the Table 12. Clinical Correlation concerning RBC
embryo proper through the circulation CLINICAL CORRELATION
• At 5 weeks gestation Patau Syndrome Presence of Gower Hgb
o BFU-E appears in fetal liver Increased levels of Hb
o CFU-E evident later on Homozygous α-Thalassemia
Portland
• At 7 weeks gestation Hemolytic anemias, leukemia,
Moderate elevations of HbF
o Hematopoietic progenitors no longer in yolk sac aplastic anemia
Causes mild to moderate
Note: Until 12 weeks of gestation: circulation of the Yolk sac Heterozygous β-Thalassemia
microcytic anemia
primitive erythroblasts Normal; NADIR – stimulation of
erythropoiesis for an increase in
2. Hepatic Physiologic anemia
EPO production corresponding
• Starts 5th – 6th weeks: liver increases in size to hemoglobin rise to normal
• Source of RBC during 9th to 24th weeks of gestation Caused by blood loss, iron,
• Smaller the yolk sac megaloblasts folate, cobalamin, vit E, protein
• Fetal liver – derived erythroid progenitors differentiate in Anemia deficiency, infection, bone
vitro with EPO (adult bone marrow-derived BFU-E requires marrow failure, and marrow
EPO & IL-3) transplant.
• Includes myeloid and lymphoid lineages (WBC’s) Physiologic jaundice due to
Neonatal Jaundice immature bilirubin, eventually
3. Bone marrow normalizes
• Starts 10th – 11th weeks in embryo Rh incompatibility (Rh negative
• Confined in diaphysis of long bones until 15th week Erythroblastosis Fetalis mother) or ABO
o Initially myeloid and erythroid cells are equal in incompatibility
numbers but at 12 wks = myeloid cells predominate, at
21 wks = 3 myeloid: 1 erythroid ratio (12-21 mirror lang) WHITE BLOOD CELLS
• Major site of hematopoiesis after 24th week and beyond • From myeloid stem cells – participates in phagocytosis
• Lymphoid stem cells – for immunity
E. Neonatal Erythrocytes • Low demand for neutrophils due to sterile conditions
• Shorter life span (intrauterine)
• Mean Cell Volume: Macrocytic (MCV > 100)
• Gradual decrease in size and volume A. Anatomic Sites
• Anisocytosis – variation in size (micro- or macrocytic) • Mesoblastic (Yolk sac) – does not participate in
• Poikilocytosis – variation in shape neutrophil production
• Fetal Hemoglobin is still present (O2 dissociation curve • Hepatic – few neutrophils (2nd trimester)
• shifted to the left = high affinity) • Bone Marrow – few neutrophils (8-10 wks until term)
• Kleihauer-Betke Test (Acid Elucidation Test): used in Rh o Cells possess round nuclei and myeloperoxidase –
incompatibility cases (Erythroblastosis Fetalis) G-CSF: uregulates neutrophil production (thus, mid
• Apt’s Test (Alkali Denaturation Test): NaOH dropped on trisem human fetus à low neutrophils = still low G-
blood will lyse adult RBC but not fetal RBC CSF)
o Result: Red/ Pink = fetal RBC; Yellow/Brown =
mother’s RBC Table 13. Neutrophils on different locations
Neutrophils at Bone Marrow
Table 11. Comparison of Fetal RBC to Adult RBC • Mitotic Pool – mitosis: myeloblast ® promyelocyte ®
Characteristics FETAL RBC ADULT RBC myelocyte
Hb HbF HbA • Maturation Pool – no mitosis only maturation: metamyelocyte
Contains i antigen Contains I antigen ® band cell mature neutrophil
Membrane
Less Na-K ATPase More Na-K ATPase Neutrophils at Blood
Shorter • Circulating Pool – circulating neutrophils within vasculature
Lifespan Longer (120 days)
(60 – 90 days) • Marginated Pool – neutrophils settled along the vessel walls
Low: glucose mostly in capillaries and venules. First ones to move out
consumption (low when needed by tissues.
Anaerobic
Metabolism PFK) Neutrophils at Tissue
Respiration
Mostly pentose • Stays here for 1-2 days
phosphate shunt
Poikilocytotis Uniform shape B. Immunity
Shape
(varying shape) (biconcave) • Opsonins – molecules that promote phagocytosis by
Size Macrocytic binding to foreign bodies; In infants: high for S. aureus;
More negative than low for yeast and E. coli
Charge
adults o Most common infection in newborns is group B
More prone to streptococcal, E. coli and yeast infection.
osmotic fragility – • Chemotaxis – movement of cells in response to
Osmotic Fragility
contributes to chemical stimulus
shorter lifespan
Shift to right (lower -
Oxygen Affinity Shift to left (higher)
transport)
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Table 14. Comparison between Lymphocytes FETAL HEMOSTASIS
o Increased CD4 and decreased CD8; • FUNCTION: prevent blood loss and maintain normal blood
newborns & children = high CD4:CD8 ratio volume
o function is immature
T-Lymphocytes
o increased helper T cell A. Development of Coagulation
o for antigen recognition and binding o All proteins involved in coagulation is produced in the
o antibody dependent cytotoxicity liver
o produced only In little amounts o Low Levels of Vitamin K-dependent Procoagulants:
o IgM, IgD, IgE, and IgA Factors II. VII. IX, & X (10 972)
o IgM: produced when exposed to infection o Low Levels of Vitamin K-dependent Anticoagulants:
B-Lymphocytes o IgG: same levels with mother as it can Protein S & C
pass through placenta
o IgA: from breast milk Table 17. Certain factors in comparison to adults
o IgM, D, E: cannot cross placenta FACTORS COMPARED TO ADULTS
Factor II, VII, IX, X, XI, XII REDUCED
Table 15. Clinical correlation concerning WBC Prekallikrein, HMW Kininogen,
CLINICAL CORRELATION REDUCED
Plasminogen
Neonatal Conjunctivitis From N. gonorrhea Antithrombin III, Protein C, and
REDUCED
High neutrophil levels due to Protein S
Neutrophilia
infections, tumors. steroids Factor XIII and V SAME
High eosinophils due to Plasminogen activator, FSP SAME
Eosinophilia
allergies, dermatitis parasites Clotting Factors @ 6 months SAME
Due to hypersensitivity,
Basophilia
inflammation, infection B. Disorders
Due to glucocorticoid
Basophilopenia administration and Table 18. Platelet disorders
thyrotoxicosis DISORDER DESCRIPTION
Hematologic disorders, Agglutination and phagocytosis
Erythroblastosis Fetalis
collagen vascular disease, of the infant’s RBCs
Monocytosis
granulomatous disease, and Lack of mature forms of Factors
infections Vitamin K Dependent II, VII, IX, and X (1972) and
Monocytopenia Glucocorticoid administration Coagulation Defects Beyond also Protein C;
Infancy Causes Prolonged Prothrombin
Time (PT)
PLATELETS Scurvy and Ehlers-Danlos Decreased stability of vascular
• prevents bleeding (clotting-platelet plugs) Syndrome walls
• Thrombopoietin Thrombocytopenia/-cytosis Affects the quantity of platelets
o regulates platelet production
o stimulates megakaryocyte growth Thrombasthenia Affects the quality of platelets
o stimulates proliferation of megakaryotic progenitors Defect in coagulation, high
Hemophilia
bleeding time
• Megakaryocyte – undergoes endoreduplication = large cell
and multiple nuclei; produced at yolk sac (6wks), Spleen May be secondary to lupus
(10wks), Marrow (13wks) erythematosus where immune
Aplastic anemia
system attacks healthy bone
A. Characteristics and Functions marrow stem cells
o Increased numbers of all megakaryocyte precursors
o MPV & MPC: comparable to adults Table 19. Platelet vs. Coagulation deficiency
o MPV: Decreased production = normal MPV; DEFICIENCY PLATELET COAGULATION
Increased destruction = large MPV Petechiae Frequent Never
o Normal V: 150–400 /1000µL Ecchymosis Superficial Deep
o Bleeding Time – time it takes bleeding to stop Stops with Does not stop with
Bleeding
o BT in infants is shorter than adults Pressure pressure
Resolution Immediate Delayed
B. Disorders Tissues
Skin and Mucous Muscles and Joints
Involved
Table 16. Clinical correlation concerning WBC
DISORDER EFFECT
Thrombocytopenia Low platelet levels
2.05 Introduction to Immunology
Count
Thrombocytosis High platelet levels
Thrombasthenia Defective clot retraction COMPONENTS OF THE IMMUNE SYSTEM
Loss of vascular integrity
or function leading to A. Lymphoid Organs
extravasation of blood into • Primary/central lymphoid organs – where production and
Function maturation of immune cells occur
Vascular purpura the tissues, skin and
mucosa producing o bone marrow and thymus
spontaneous ecchymoses • Secondary/peripheral lymphoid organs – where immune
and petechia cells stay and wait, after maturation, for antigens
o lymph node, spleen, MALT

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B. Immune Cells B. Complement cascade
• Lymphocytes – specific/ adaptive immunity • Initiation of complement activation – classical, MBL, and
o B-cells (bone marrow) → plasma cells → antibodies alternative pathways
o T-cells (thymus) – three types: helper, suppressor, • Early steps – C3 convertase production (C3a: increased
cytotoxic inflammation, C3b: increased opsonization and
o NK cells – T-cell; work with macrophages and phagocytosis, C5a: increased inflammation)
neutrophils but not phagocytic • Late steps – ending is either killing the pathogen or
• Antigen-presenting cells (APC) – innate immunity, increasing the removal of pathogen through phagocytosis
phagocytic
o Macrophages
o Neutrophils

C. Antigen Recognition Molecules

• Presentation of antigens
o Specific: MHCs I and II
o Innate: specific arrangement of molecules in
surface of pathogens
• Recognition of antigens
o Specific: antibody in B-cells (B-cell receptors) and
T-cell receptors
o Innate: toll-like receptors (TLRs) and mannose-
binding lectins (MBLs)
• Molecules in the blood
o Antibody and complement
Figure 7. Steps in the activation of the different complement
D. Antigens cascades.
• Specific arrangement/ conformation – part recognized by
the innate immune system C. Adaptive Immunity
• Epitope (arrangement of amino acids of the antigenic • Stimulated by exposure to infectious agents
determinant) – part recognized by the adaptive immune • Respond more vigorously to repeated exposures to the
system; interacts with an antibody same microbes, has memory
• Gaining adaptive immunity:
INNATE IMMUNITY 1. Active immunity
§ Natural active: through infection
• Immediate response, first line of defense § Artificial active: through vaccination
• Nonspecific, no memory 2. Passive immunity ® no memory of the pathogen
• Components: § Natural passive: transfer of maternal antibodies
o Anatomical barrier: tight junctions, mucus, commensal to the fetus (IgG)
bacteria § Artificial passive: transfer of immunity to
o Physiological barrier: chemicals, cough reflex, fever unimmunized individuals using antiserum or
o Bactericidal secretions: lysozyme, transferrin, cells from immunized patients
lactoferrin
o Cytokines: interleukins; IL-1 and IL-6 induce fever, IL-2 Types of adaptive immunity
activates all other T- and B-cells, interferon γ kills viruses
o Chemokines: induce direct chemotaxis in nearby cells, Table 21. Humoral vs. Cell-mediated immunity
call the cells to the area of invasion HUMORAL CELL- MEDIATED
o Phagocytic cells: macrophages, neutrophils, NK cells intracellular
o NK cells: distinguish infected from uninfected cells, Target extracellular phagocytosed microbes
contains granzymes that can lead to apoptosis of microbes microbes microbes in replicating within
infected cells, acted upon by IFN-2 and IL-2 macrophages infected cell
o Effector proteins in circulation: complement system, Responding
B-Cells helper T-Cells cytotoxic T-Cells
mannose-binding lectin (collectin), C-reactive protein lymphocytes
(pentraxin) Transferred serum
T-Cells T-Cells
o Cell-associated pattern recognition molecules: TLRs by (antibodies)
blocks activates kills infected cells
Table 20. Toll-like receptors and their ligands infections macrophages and eliminates
TLR Ligand Function and to kill reservoirs of
TLR-1 dimer peptidoglycan, eliminates phagocytosed infection
TLR-2/ TLR-6 dimer lipoproteins extracellular microbes
TLR-3 dsRNA (virus) microbes
TLR-4 dimer (plus LPS (Gram-negative
CD14) bacteria) Phases of adaptive immunity
• Recognition phase – antigen recognition, processing, and
TLR-5 flagellin
presentation
unmyelinated CpG
TLR-9 • Activation phase – lymphocyte activation, proliferation and
DNA (virus)
differentiation of effector cells, clonal expansion
A. Inflammatory reaction • Antigen elimination phase – humoral and cell-mediated
immunity
• release of cytokines and chemokines → vasodilation,
increased vascular permeability → inflammatory cells
migrate into invaded tissue
• recall: rubor, calor, tumor, dolor, loss of function

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 o B cells – antibody production will neutralize antigen, coat
them for opsonization; stimulate mast cell degranulation
® release of mediators ® ­ vascular permeability of the
capillaries
o T Cells – CD4+ helper T cells secrete cytokines to
enhance phagocytosis by macrophages and stimulate the
inflammatory response; CD8+ cytotoxic T cells
participates in directly killing of infected cells
• Contraction phase – hemostasis, apoptosis
• Memory phase – antibodies will remember antigens; more
intense response during second exposure; presence of
surviving cells after apoptosis are memory cells

Figure 9. Classes of lymphocytes.

Table 22. Summary of the two types of immunity

CHARACTERISTICS INNATE ADAPTIVE
For antigens of
For structures shared
Specificity microbes and for
by groups of related
non-microbial
microbes
antigens
Very large; receptors
Diversity are produced by
Limited; germline
somatic
encoded
recombination of
gene segments
Figure 8. Phases of adaptive immunity. CD8+ cytotoxic T cells
recognize peptides expressed by Antigen Presenting Cells (APC) Memory - +
Non-reactivity to
with Major Histocompatibility Complex (MHC) which regulates YES YES
self
immune response. MHC Class I (present in all nucleated cells;
Skin, mucosal Lymphocytes in
CD8+ cytotoxic T lymphocytes recognizes viral polypeptides).
Cellular and epithelia; epithelia; antibodies
MHC Class II (present in B cells, macrophages, dendritic cells, chemical barriers antimicrobial secreted at epithelial
and endothelial cells; CD4+ helper T cells recognize bacterial chemicals surfaces
antigens found on surfaces of infected cells). Blood proteins Complement, others Antibodies
Phagocytes
Cells of adaptive immunity Cells (macrophages, Lymphocytes
neutrophils), NK cells
A. Mononuclear phagocytes – effector cell of cellular immunity
o In natural immunity: phagocytose pathogens, produce ANTIBODIES/ IMMUNOGLOBULINS
cytokines for inflammation • Antibodies
B. Dendritic cells o Proteins that recognize and bind to a particular antigen; with
o Accessory cells (in interstitium) – efficient APC to CD4+ very high specificity
helper T cells o One virus/microbe may have several antigenic determinant
o Follicular dendritic cells (in germinal centers of lymphoid sites, or epitopes, to which different antibodies may bind
follicles) – trap antigens bound to antibodies of o Each antibody has at least two identical sites (antigen-
complement products; APC to B cells binding sites or paratopes) where the hypervariable region is
C. Lymphocytes – produce specific receptors for antigens found
o B lymphocytes – mature in bone marrow; involved in • Structure:
neutralization of microbe, phagocytosis, opsonization, o Monomer – a flexible Y-shaped molecule with two identical
and complement activation heavy chains linked by disulfide bridges and two identical
o T lymphocytes – mature in the thymus; CD4+ T (T light chains
helper) cells, regulatory T cells (T-reg), CD8+ T (cytotoxic o Variable regions (Fab) – contain the antigen-binding sites
T) cells o Constant regions (Fc) – fragment that binds with mast cells
and complement
• Classes of Immunoglobulins
o From most abundant to least: GAMDE
• IgG – preGGy
• IgM – Mauuna, Malaki (primary response; largest)
• IgA – lAway, luhA, gAtas, pAwis, semilyA (secretions)
• IgE – allergEe (hypersensitivity reactions)
• IgG and IgM – activate complement
• IgG, IgA, IgE – antibody dependent cell mediated
cytotoxicity

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Table 23. Immunoglobulins function summary table
Immunoglobulin Major Functions
2.06 Respiratory Physiology I
o Main antibody in secondary response
o Opsonizes bacteria (making them easier FUNCTIONAL ANATOMY
to phagocytize)
IgG o Fixes complement (which enhances A. Tracheobronchial tree
bacterial killing) • Conducting Zone: conducts air to respiratory zone – no
o Neutralizes bacterial toxins and viruses gas exchange. Note: terminal & distal ends contain no
o Can CROSS THE PLACENTA cartilage so they are easily collapsible
o Secretory IgA prevents attachment • Respiratory Zone: fundamental unit of gas exchange
IgA bacteria/viruses in mucous membranes (~23 generations of respiratory bronchioles)
o Doesn’t fix complement
o Produced in the primary response to an
antigen
IgM o Fixes complement
o Doesn’t cross placenta
o Antigen receptor on surface of B cells
o Uncertain
IgD o Found in the surface of many B cells as
well as in serum
o Mediates immediate hypersensitivity (by
causing release of mediators from mast
cells and basophils upon exposure to
antigen [allergen])
o Defends against worm infections by Figure 10. The conducting and respiratory zones
IgE
causing release of enzymes from
eosinophils B. Respiratory Muscles
o Does not fix complement
o Main host defense against helminth Table 25. Actions of respiratory muscles in normal v. forceful breathing
infections Normal Breathing Forceful Breathing
Contraction of
Inspiration Contraction of
Diaphragm – most
APPLICATIONS IN MEDICINE Active process that Accessory
important
• Vaccination: basis is mostly the development of immunologic expands the thoracic Muscles:
memory cavity to SCM
Contraction of
accommodate the Scalene
• Cancer treatment: monoclonal antibodies (targeted therapy) external
inspired air Pectoralis Major
against specific antigen of the tumor intercostals
• Transplantation and graft rejection: the goal is to prevent Contraction of
rejection of the graft by giving drugs that will limit the immune Accessory
Passive process: Muscles:
response by limiting inflammatory action
relaxation of muscles Internal Intercostals
• Autoimmune disease Expiration
(esp. diaphragm*) + Abdominal wall
~usually passive
• Continuous production of response that lead to chronic elastic recoil of lungs muscles (eg. rectus
inflammation = enough to expel air abdominis)
• Launch immune response against self-antigens à Aids in depressing
the rib cage
• (e.g. Incompletely treated streptococcal infection cross reacts *Relaxation of diaphragm: causes its upward movement causing
with a protein of the valve of heart – Rheumatic Heart an increase in intrapleural pressure
Disease) • Increase in pressure is transmitted to alveolar ducts and alveoli
• Hypersensitivity reactions: very intense response against causing them to compress (air leaves lungs)
antigen • Recoil forces from alveoli promote expiration

Table 24. Summary of the four types of hypersensitivity PRESSURE AND VOLUME CHANGES IN
Mode of Pathologic LUNGS & THROACIC CAVITY
Type Tissue injury • Respiratory Cycle
mediation Mechanism
mast cells and their o Single cycle of inhalation and exhalation
immediate mediators cause o Pressure gradients are created between the environment
Type 1 IgE and alveoli that allow bulk flow of air in and out of lungs
hypersensitivity vasodilation and
anaphylaxis o Pressure gradients are generated by:
IgM and IgG § Contraction of diaphragm and external intercostals
antibody- opsonization (inspiration)
Type 2 against cell
mediated phagocytosis § Elastic recoil or lungs (expiration)
surface
immune Complement and Fc
immune complexes of receptor-mediated
1. Intrapulmonary pressure – pressure inside lungs,
Type 3 complex- circulating recruitment and includes all airways
mediated antigens activation of Note: there is a negative pressure between the parietal and
IgM and IgG leukocytes visceral pleura, being more negative at the apex
2. Trans pulmonary pressure – whole pressure of the
Macrophage
activation
lungs, relative to the environment; keeps the lungs
CD4+ helper T-
inflated and prevents their collapse
delayed cells and CD8+ cytokine-mediated
Type 4 3. Intrapleural pressure – pressure between thoracic
hypersensitivity cytotoxic T-cells inflammation
causing lysis
cavity (parietal pleura) and lungs (visceral pleura)
direct target cell
containing pleural fluid (-10 cm H2O at apex, -2.5 at base,
killing
ave. -4 to -5)

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 Note: Air viscosity and Airway length basically are
unchanging, Airway diameter is highly variable – has great
impact because radius is raised to 4th power

• Compliance Resistance: intrinsic resistance to

stretching of the alveolar air spaces and lung
parenchyma
• Tissue resistance: friction that occurs when the pleural
surfaces glide over each other as the lungs inflate

B. Sources of Resistance During Expiration

• As the volume of the thoracic cavity decreases during
Figure 11. Pressures present during a respiratory cycle. expiration, the intrathoracic pressure increases

A. Respiratory Mechanics
1. Transairway pressure: pressure at the airway opening –
pressure in the lungs
o generates flow through the airwa
2. Transthoracic pressure: pressure in the lungs –
pressure on the body surface
o generates expansion of elastic chamber
3. Transrespiratory pressure:
o pressure at the airway opening – pressure on the
body surface
o trans airway pressure + Trans thoracic pressure
o required to generate inspiration
Note: The “airway-pressure” gauge on a positive-pressure
ventilator displays trans respiratory pressure
Note: Boyle’s Law: Pressure and Volume are inversely related
• Increase in pressure compresses airways and reduce
airway diameter (primary source of resistance to airflow)
• Radial Fibers: exert traction on small airways to prevent
collapse
C. Tissue Resistance
• Frictional resistance as pleural surfaces glide over each
other
o Small amount of pleural fluid in space acts as
lubrication
o Normal: 5% work of breathing
D. Contribution of Airways to Resistance

B. Pneumothorax Table 27. Large vs. Small airways

Large Small
Table 26. Types of Pneumothorax
Closed Open Tension Contributes to most of total Consists of: Terminal bronchiole,
Air in Pleural Space Increasing air in airway resistance respiratory bronchioles and
Air in Pleural alveolar ducts
(no external wounds) pleural space and
Space
Cancer/ cystic unable to escape
(stab wounds) Arranged in Series Arranged in parallel
fibrosis (lung laceration)
Pleural cavity Pleural cavity Pleural cavity
Turbulent flow Greater total cross-sectional
pressure < pressure = pressure >
area (compared from which they
atmospheric atmospheric atmospheric
branched)
pressure pressure pressure
Laminar flow
COMPLIANCE AND RESISTANCE
E. Work of Breathing
A. Sources of Resistance in Inspiration
• Pressure-volume work performed in moving air into and
out of lungs
• Most work is performed during inspiration (because
expiration is passive)
• Work is needed to overcome the 3 primary sources of
resistance encountered during inspiration
• Compliance Resistance (Work): work needed to
overcome intrinsic elastic recoil
o Approx. 75% of the total work of breathing

Figure 12. Lung volume vs. Pleural Pressure during Inspiration.

• Airway Resistance: friction between air molecules and

the airway walls
• Normal: Approx. 20% of work in breathing
• Air is essential a low viscosity fluid, airflow resistance is
equated to resistance of a fluid travelling through a rigid
tube Figure 13. Pressure vs. Volume during airway resistance.
"#$
• Poiseuille’s Equation: R =
%&'
Note: airway resistance widens the loop (expiratory resistance is
more common)

14 of 22
 F. Pulmonary Compliance (C)
• change in volume (∆V) required for a fractional change of
pulmonary pressure (P)
o (C) = ∆V/∆P
• Measure of lung distensibility – lungs should be very
compliant
G. Pulmonary Elastance
• property of lungs that makes it resist deformation (Highly
elastic structures are difficult to deform)
o E = ∆P/∆V
• With increase in elastance, greater pressure changes will
be needed to distend the lungs
H. Surfactant and Surface Tension
• Fluid lining membrane is still primarily water with inherent
forces of attraction which generate surface tension that
contributes to a collapsing pressure (helps collapse alveoli)
• Laplace’ Law: CP = T/R (R is alveolar radius)
Note: Smaller radius, larger collapsing pressure
• Surfactant in lungs: complex phospholipid secreted onto
the alveolar membrane by type 2 epithelial cells.
o minimizes interaction bet. alveolar fluid and alveolar air
o reduces surface tension
o increases lung compliance
o reduces the work of breathing
o reduced compliance resistance (work) of lungs
o Balances the collapsing pressure in lungs
B. Forced Expiratory Volumes and Capacities
• Sum of 2 or more lung volumes = Lung Capacities
1. Functional Residual Capacity – volume of lung at
rest; the equilibrium point at which the elastic recoil of
the lungs is equal and opposite to the outward force
of the chest wall
• FRC = RV + ERV
• Mixing of small TV and large FCR prevents
fluctuations in alveolar oxygen tension with
every normal breath
2. Inspiratory Capacity – max volume of air that can
be inhaled AFTER normal tidal expiration
• IC = TV+ IRV
3. Vital Capacity – max volume of air that can expired
after maximal inspiration aka Forced Vital Capacity
• VC = IRV + TV + ERV
4. Total Lunch Capacity - max volume of air in lungs
after max inspiration
• TLC = IRV + TV + ERV + RV

PULMONARY FUNCTION TESTS

Figure 15. Normal spirometry tracing.

Figure 14. Normal spirometry tracing.

A. Static Lung Volumes

• comprises several individual pulmonary volumes and
capacities, measured by a spirometer:
a. Tidal Volume (TV) – Varies with such factors as
age, activity level, and position (ave. = 0.5 L)
b. Inspiratory Reserve Volume (IRV) – max volume of
air that can be inspired beyond a normal tidal
inspiration (ave. = 3 L). Factors affecting it: 1lung
volume after inspiration, 2compliance, 3muscle Figure 16. FEV1/ FVC Ratio per volume exhaled.
strength, 4comfort, 5flexibility of skeleton and posture
c. Expiratory Reserve Volume (ERV) – max volume of
• Forced Expiratory Volume 1 (FEV1): max amount of air
air that can be exhaled after a normal tidal expiration
exhaled in 1 sec after maximal inspiration
(ave. = 1.1L). Affected by same factors as IRV &
o 80% of Forced Vital capacity (FVC) in health adults
abdominal muscles of respiration
aka FEV1/FVC ration
d. Residual Volume** (RV) – amount of air remaining
o Clinically useful in distinguishing Restrictive vs
in lungs after maximal forced expiration (slightly
Obstructive lung diseases
above 1L) Reason: (1) cartilages in major airways
prevent collapse & (2) not all alveolar units get to
Table 28. Obstructive vs. Restrictive lung disease
empty before the small conducting airways collapse
Normal Lungs Obstructive Restrictive
§ Minimal volume – a component of RV, amount of
air in lungs IF allowed to collapse (30-120mL);
FEV1/FVC= 0.80 FEV1/FVC < 0.80 FEV1/FVC > 0.80
can’t be measured in healthy person. If allowed to
collapse, there is still air remaining due to the
surfactant coating preventing alveolar surfaces to
collapse
**only one that can’t be directly measured with
volume recorders

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Table 29. Different types of Dead Spaces 1. ZONE 1 (Apical region)
total volume of lung space that does not participate in • No blood flow: pulmonary capillary pressure never rises
Physiologic gas exchange higher than the alveolar air pressure, so the capillaries
Dead Space are crushed and the blood flow is greatly reduced
sum of the anatomic and alveolar dead spaces • PA > Pa > Pv
Conducting airways – before inspired air reaches
• Occurs in abnormal conditions (either: pulmonary
terminal respiratory airways; volume of conducting
systemic arterial P is too low due to severe blood loss OR
Anatomic airways that don’t exchange oxygen with the
Dead Space pulmonary capillary blood
alveolar P is too high due to breathing against positive air
pressure
1 mL per lb. of body weight for thin adults 2. ZONE 2
Volume of alveoli that are ventilated but not supplied • Intermittent/Moderate blood flow
Alveolar with blood, eg. Pulmonary embolism • Pa > PA > Pv
Dead Space • Blood flows only at systole: systolic arterial P rises higher
Air here doesn’t contribute to alveolar PACO2 than alveolar air P, but diastolic arterial P falls below
In healthy adults, it should be near 0 alveolar air pressure
• Occurs normally in apices of lungs
C. Peak Flow Meter 3. ZONE 3
• Measures: speed of expiration • Continuous blood flow: arterial P and pulmonary capillary
o Low values imply that airways are constricted pressure remain greater than alveolar air pressure at all
o Reference values based on general population times
• Pa > Pv > PA
2.07 Respiratory Physiology II • Occurs in apices and bases of lungs
• Better flow because of gravity
CIRCULATIONS IN RESPIRATORY SYSTEM
Table 31. Apex and Base comparison
APEX BASE
Table 30. Pulmonary vs. Bronchial circulation
PULMONARY CIRCULATON BRONCHIAL CIRCULATION
Intrapleural
More negative More positive
Pressure
• Low pressure (P), high-flow • High P, low-flow circulation
Alveoli
circulation (low P circulation: ¼ • Part of systemic circulation More distended Some not distended
of systemic circulation) Characteristics
• 1-3% of CO
• Removal of CO2; oxygenation • Lung metabolic demands are Blood Flow Lesser Greater
before blood is returned to low (lung parenchyma gets O2 Alveolar
Lesser Greater
systemic circulation from inspired air) Ventilation
• Receives all cardiac output • Bronchial vein routes V/Q Ratio High Low
(CO) o Pulmonary veins ®
• High hydrostatic P promotes contributing to anatomical VENTILATION/ PERFUSION (V/Q) RATIO
leakage of fluid shunts • Alveolar ventilation : pulmonary blood flow
• Pulmonary blood vessels able o Compromised Pulmonary • Alveolar vent = 4200 mL/min
to distend/recruit blood vessels circulation ® increases • Pulmonary blood flow = 5000 mL/min
with increase in blood volume bronchial flow; vice versa • Ideal ration V/Q = 0.84
• Only artery (pulmonary a) that • Hypoxia à vasodilation
carries deoxygenated blood • Ventilation rate
• Symmetrical distribution of o Volume of air moved in and out of lungs per unit time
pressures o Expressed in 2 ways: minute vent. & alveolar vent.
• Hypoxia à vasoconstriction o Takes RR into consideration

Hypoxic Vasoconstriction Alveolar PO2 and PCO2

• Decrease in O2 tension
• Systemic arterioles dilate to increase blood flow
• Systemic arterioles constrict to direct blood to area of the
lungs with higher ventilation
• NE to alpha 1 receptors: vasoconstriction
• NE to alpha 2 receptors: vasodilate
• Ach to muscarinic 3 receptors: no release, vasodilate
• Determined by V/Q rate
• Inversely related thru alveolar vent
• High V/Q ® Higher PAO2 and Lower PACO2
o Hyperventilation PACO2 < 40 ® ­ alveolar O2 tension
(taking more air than needed)
• Low V/Q ® Lower PAO2 and Higher PACO2
o Hypoventilation PACO2 > 40

ZONES OF THE LUNGS Notes

• Supine àblood flow is nearly uniform • V/Q=0 ® perfusion, no ventilation
• Standing à blood flow uneven due to gravity • V/Q=high ® ventilation > perfusion
o Blood flow lowest at apex • V/Q=low ® perfusion > ventilation
o Highest at the base V/Q=infinity ® no perfusion, with ventilation
• Intrapleural pressure
o More negative: apex
o More positive: base
• Blood flow: greater in base than apex
o V/Q ratio low at base, high at apex
o Basal end overwhelmed by perfusion = more blood at
that area due to gravity

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 GAS TRANSPORT B. Diffusion of Gases Through the Respiratory Membrane
• Heme can bind reversibly • Factors affecting rate of gas diffusion through respiratory
o Ferrous state iron allows for rapid oxygenation and membrane:
deoxygenation a. Membrane Thickness
o Thickness increases, rate of diffusion
A. Oxyhemoglobin Dissociation Curve decreases
b. Membrane Surface area
o Surface area of the membrane decreases,
rate of diffusion decreases
c. Diffusion coefficient of the gas in the substance of
the membrane
o The greater the diffusion coefficient, the
greater the rate of diffusion
o Depends on gas solubility in the membrane
o Small molecule that is highly soluble diffuses
fast
d. Partial pressure difference of the gas between the
two sides of the membrane
o Pressure difference- diff between partial P of
Figure 17. Oxyhemoglobin Dissociation Curve gas in alveoli and partial P in the pulmonary
capillary blood
o Sigmoidal C. Diffusion Capacity (Transfer Factor)
o Shows Hgb affinity for O2 • Volume of a gas that will diffuse thru the membrane each
minute for a partial P difference of 1 mmHg
Table 32. Direction of the Oxyhemoglobin Dissociation Curve • Diffusion Capacity for CO (DLCO) is measured as the
TO THE LEFT TO THE RIGHT index for the diffusion capacity because its uptake is
• O2 not needed • O2 needed diffusion limited
• ­ affinity due to decreased • ¯ affinity, increase need in D. O2 and CO2 Lung Exchange
need tissues • Perfusion Limited
• tightly bounded to Hgb • ­ CO2 tension o Partial pressure of gas in the blood leaving the
• ¯ CO2 tension • ­ temperature capillaries has reached equilibrium with alveolar gas
o Limited by amt of blood perfusing alveolus
• ¯ 2,3-BPG • ¯ pH
o O2 and CO2 have greater affinity having a rapid rate
• ¯ temperature • hyperthermia of equilibration (usually within 0.25 seconds)
• ­ pH • hypercarbia
• hyperventilation • Diffusion Limited
o Gas transport rate limited by the diffusion of rate of
B. Bohr Effect the gas across the alveolar membrane
• ¯ O2 affinity of Hgb when pH falls o Diffusion limited gas does not reach equilibrium with
• CO2 ® Carbonic acid ® HCO3- and H+ the alveolar pressure
• ­ H+ = ¯ pH = Hgb release O2 • O2
• Promotes O2 transport o Limited by perfusion at rest; diffusion limited when
there is an activity
C. Haldane Effect o Lots of blood perfusing the alveoli= lot of gas
• ­ affinity of deoxygenated Hgb to bind and carry CO2 transported and vice versa
• Promotes CO2 transport • CO2
• Forms carbamino compound o Diffusion limited due to greater affinity for Hgb
o Greater rate of diffusion in blood vs O2, but has a
DIFFUSION lower membrane-blood solubility ratio= consequently
takes same amount of time to reach equilibrium
A. Fick’s Law
• Rate of diffusion across membrane SHUNTS
• Gas volume per minute is directly proportional to the
surface area, diffusion coefficient, and partial pressure of A. Anatomical Shunt
gas • Deoxygenated blood mixes with the oxygenated blood
• Vgas = As x D x ∆ P / T • Despite shunted blood having elevated CO2, arterial
• Proportional to: concentration gradient, gas solubility, Pco2 does not increase
surface area • Central chemoreceptors responds to CO2 elevations by
• Inversely proportional to: thickness of membrane, increasing ventilation and reducing arterial PCO2 to
molecular weight normal range
B. Physiological Shunt
Factors Affecting Rate of Diffusion in a Fluid • AKA venous admixture
1. Gas solubility in the fluid • Pathological: blood passes thru but not properly
2. Cross-sectional area of fluid oxygenated
3. Distance wherein gas must diffuse
• Leads to ventilation-perfusion imbalance ® hypoxemia
4. Molecular weight of gas
5. Temp of fluid (in the body, tem remains constant, usually
C. Right-To-Left Shunt
need not be considered) • Deoxygenated blood from right side of heart dilutes the
oxygenated blood on the left side of the heart
Simple Diffusion- mechanism for gas exchange in both lungs D. Physiological Shunt vs Physiological Dead Space
(between blood and air) and tissues (blood and tissues) • Alveoli w/in dead space is ventilated, but not properly
perfused

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 CLINICAL CORRELATION CENTRAL CONTROLLERS: BRAINSTEM

Table 33. Hypoxia vs. Hypoxemia • Respiratory center: pons and medulla
HYPOXIA HYPOXEMIA o Dorsal Respiratory Group (DRG) – dorsal part of
• ¯ O2 delivered to tissues • ¯ blood O2 medulla; for inspiration; major component: Nucleus of
(O2 gets to the tissue but 1. Anemic Hypoxia – not tractus
not utilized) enough Hgb to carry O2 o Ventral Respiratory Group (VRG) – ventrolateral part
• Anoxia: complete O2 2. Ischemic/Stagnant of medulla; for expiration; major components: Nucleus
deprivation Hypoxia – Blockage in the retrofacialis and Nucleus ambiguous
circulation due to o Pneumotaxic Center – superior to pons; controls rate
thrombus/embolus and depth of breathing
• Inspiration
HYPOXIA/HYPERCARBIA o Ramp-like due to gradual increase in the discharge of
• Increase in arterial CO2 tension usually due to pulmonary action potentials
embolus obstructing blood flow o Active process
• Hypoventilation: will decrease pulmonary artery O2 and then o Occurs when there is a change in pressure
increases CO2 • Expiration
o Total cessation of inspiratory effort (flat line) and is
Table 34. Respiratory: acidosis vs. alkalosis passive during quiet breathing
RESPIRATORY ACIDOSIS RESPIRATORY
ALKALOSIS MEDULLARY RESPIRATORY CENTER
• By hypoventilation • Hyperventilation • located in the medulla oblongata
• Excess CO2 • Low levels CO2 • Two main parts:
• ¯ HCO3-:PCO2 ratio • ­ HCO3-:PCO2 ratio o Ventilator pattern generator – sets rhythmic pattern
o Integrator – controls generation of the pattern
Table 35. Respiratory Failure Types
TYPE 1 TYPE 2 A. Dorsal Respiratory Group of Neurons
• Hypoxemia w/o hypercarbia • Hypoxemia w/ hypercapnia • Mainly inspiratory
• Caused by lung failure ® gas • High arterial CO2 tension due • Responds to changes in pH, pCO2 and pO2, detected by
exchange failure to ventilation/pump failure peripheral chemoreceptors
• Low arterial O2 tension with • CO2 buildup can’t be • Visceral efferent fibers from CNIX and CNX
normal CO2 tension eliminated • Basic rhythm of respiration
• By pneumonia, pulmonary • By COPD, chronic bronchitis,
edema asthma B. Ventral Respiratory Group of Neurons
• Contain both inspiratory and expiratory neurons
• Mainly for expiration
2.08 Regulation of Respiration • Not active during quiet, normal breathing
• Has an overdrive mechanism with 3 regions:
MAIN GOALS OF RESPIRATION o Rostral VRG - expiratory
o Intermediate VRG – inspiratory
A. Sufficient Alveolar Ventilation § Pre-Botzinger Complex - pacemaker
• Computation: § Nucleus Ambiguous
(Tidal Volume - Dead Space) x Respiratory Rate § Nucleus Para-Ambigualis
• It is the amount of fresh gas that goes in and out of the o Caudal VRG - expiratory
alveoli
Arterial Blood Gas Values APNEUSTIC CENTER
o pH: 7.35 – 7.45 • Located in the lower pons
o pCO2: 35 – 45 mmHg • Inhibitory of impulses from the pneumotaxic center
o pO2: 80-100mmHg • Stimulates inspiration, producing a deep and prolonged
B. Adaptability inspiratory gasp
• Allow adaptation to other activities sharing anatomical • High tidal volume and low respiratory rate
structures with the lung. • Slow, deep breathing may lead to hypercapnia
C. Maintenance of Acid-Base Balance in the Brain
• Regulation of arterial pCO2 PNEUMOTAXIC CENTER
o Most potent stimulus for breathing • At upper pons or pontine respiratory group
o Affects central chemoreceptors • Regulates inspiratory volume and respiratory rate by
• The respiratory system is the fastest system that will inhibiting respiration
compensate for metabolic acidosis. • Types of breathing: (á respiratory rate and â tidal
volume)
MECHANISM OF RESPIRATION o Compromised ventilation
• Generation of automatic rhythm regulated by the respiratory o Fast and shallow breathing
center in the brainstem
o By producing a rhythmic discharge, motor neurons that
innervate the respiratory muscles are stimulated to
produce spontaneous respiration.
• Major sites of Ventilatory Control
o Respiratory Control Center
o Central Chemoreceptors
o Peripheral Chemoreceptors
o Pulmonary Mechanoreceptors/sensory nerves

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 EFFECT OF BRAINSTEM SECTIONING ON RESPIRATION • Carotid bodies (CN IX)
• Vagus nerve – carry stretch impulses o Sensitive to pO2 and pH changes
• Aortic bodies (CN X)
o Sensitive to pCO2 and PO2 changes

B. Chemical Controls
• Controlled by pO2 levels by Peripheral Chemoreceptors
o Normal: 80-100 mmHg
o Acclimatization: adaptation to chronic low levels of
O2
• Controlled by pCO2
o Normal: 35-45 mmHg
o More potent stimulant
o An increased arterial pCO2:
§ Higher than normal: hypercarbia
§ > 90mmHg ® coma
§ > 180 mmHg ® death
o An decreased arterial pO2
Figure 18. Brainstem sectioning with and without vagal § Rapid increase in minute ventilation
§ No limit
afferent feedback
• Controlled by H+ ions
A. Section above the pons: o Metabolic acidosis with diabetes
• Normal pattern; Removal of afferent input ® enhanced o Peripheral chemoreceptors stimulated
o Reflex-induced hyperventilation
inspiration
• Hering-Bauer reflex is abolished
Lung Receptors
• Vagi cut: Increased tidal volume, decreased frequency
A. Pulmonary Mechanoreceptors
B. Section at the midpontine level:
• Slow Adapting Pulmonary Stretch
• Increases depth of breathing
• Impulses through myelinated vagus fibers
• Elimination of central and peripheral inhibition of
• Located in the extrathoracic trachea down the
inspiration
intrapulmonary bronchi
• Vagi cut: apneustic breathing
I. Hering-Breuer Inflation reflex (Inhibito-Inspiratory
C. Section between medulla and pons:
Reflex)
• Irregular respiration
• Stimulated by increase in lung volume
• Vagi cut: gasping patterns; little effect
• 800-1500 mL in adults
• Inhibits tidal volume and over-distention
D. Section between spinal cord and medulla:
• Cessation of inspiration
• Respiratory arrest
II. Hering-Breuer Deflation Reflex (Excito-inspiratory
reflex)
CORTEX: VOLUNTARY CONTROL OF BREATHING
• Stimulated by decreased stretch receptor activity
• Voluntary control – can either hyper/hypoventilate at will
through descending pathways from the cortex to the motor • Increased ventilator rate (hyperapnea)
neurons of respiratory muscles • Periodic, spontaneous deep breaths, prevent
Atelectasis (alveolar collapse)
• Can bypass the medulla but only up to certain extent • Maintains functional residual capacity
o Breath-holding – increase in CO2 until reaching III. Paradoxical reflex
threshold will lead to overriding voluntary control • Inspiratory/Provoked Augmenting Reflex
o Deliberate hyperventilation • Mechanism for first breath and sighing
§ Greatest minute ventilation • Occurs when vagal function is partly blocked due to
• Other parts of the brain: cold temperatures
o Limbic system • Increase in inspiration ® very deep inspiration
o Hypothalamus – emotions (rage and fear) IV. Diving Reflex
• Apnea and bradycardia occur
SENSORS • Protects individuals from aspirating water in cases of
initial drowning
A. Chemoreceptors
• Respond to changes in CO2, O2, and H+ ions B. Irritant receptors (rapidly adapting pulmonary stretch
receptors)
I. Central chemoreceptors • Stimulation leads to airway resistance, reflex apnea
• Increase in pCO2 and H+ ® stimulate breathing sneezing, and coughing
• Decrease in pCO2 and H+ ® inhibit breathing • Stimulated by dust, smoke and cold air
• Indirectly stimulated by increase in pCO2 • Detects histamine and other agents
• H+ ion cannot cross the blood brain barrier • Cause hyperapnea

II. Peripheral Chemoreceptors C. J-receptors (Juxtaalveolar/ Juxtacapillary receptors)

• Stimulated by: • Stimulated by chemicals, engorgement of pulmonary
o Increased H+ concentration; Metabolic Acidosis capillaries, increase in ICF volume
o Increase in arterial pCO2 • Rapid shallow breathing in heart failure and other lung
o Decrease in arterial pO2 (<60 mmHg); Hypoxia diseases

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 OTHER RECEPTORS 2.09 Pediatric Respiratory Physiology
• Nose and upper airway receptors:
A. Cough Reflex
FIVE STAGES OF LUNG DEVELOPMENT
• Negated by alcohol
• Stimulated by lung hyperinflation *mnemonic: EPCTA: Every Premature Child Takes Air *
• Glottis closes when taking deep breaths ® air from
lungs is forced against glottis ® glottis opens Table 36. The Stages of Lung Development
suddenly STAGES DESCRIPTION
B. Sneeze reflex
• Ventral outpouching of the primitive gut
• Stimulated by irritation of nasal passageways; uvula is EMBRYONIC
• Not capable of gas exchange
depressed ® allow air to rapidly pass through nose STAGE
• Primary bronchi elongate in the mesenchyme
(Day 26 - Day 52)
C. Immediate cessation of breathing and divide into 2 main bronchi
• Triggered by noxious stimuli or by chronic smoking
• Entire conducting airways is formed
D. Laryngeal Spasm
• Primary bronchioles give rise to air exchanging
• Choking portion of the lungs
E. Joint and muscle receptors • Terminal bronchioles is formed for anatomic
PSEUDOGLAN-
• Respond to changes in length and tension of DULAR STAGE dead space
respiratory muscles (Day 52 – Week 16) • Mesenchyme ® cartilage, smooth muscle, & CT
• Arterial Baroreceptors – an increase in BP ® reflex: • Trachea and foregut separate
hypoventilation • Diaphragm is formed
• Pain and Temperature – increase ® hyperventilation • Week 20-24: babies are surfactant-dependent;
able to retain air at end-expiration
EFFECTORS • Week 26-28: babies have alveolar structure
• Spinal cord: axons from DRG, VRG and cortex descend in and produce surfactant
white matter to influence the muscles of respiration (must CANALICULAR
• Development of terminal air sac or primitive
coordinate). STAGE
(Week 16 – Week 28)
alveoli (respiratory bronchioles with 2-3 thin-
• Responsibility of the central controller walled dilation)
• Epithelial growth > mesenchymal growth
CLINICAL CONSIDERATIONS • Bronchial tree develops a more tubular
appearance
A. Sleep Apnea Syndrome • Babies are capable of breathing but initially
• Cessation of breathing are abnormally prolonged and labored
SACCULAR/ • Further development of respiratory portion –
more frequent during sleep; caused by obstruction of TERMINAL SAC
upper airways or impaired CNS respiratory drive responsible for adequate gas exchange
STAGE
• Obstructive sleep Apnea – most common; revolves (Week 28 – Week 36)
• Terminal airways form saccules
around physical obstruction of the upper airway or • Surfactants are immature containing
intracellular glycogens
hypopharynx
• Snore ® Stop Breathing ® SNORT ® Wake Up ® • Mature surfactant (completed protein &
phospholipid components)
Sudden Recovery/ Back to Normal Breathing ® Back to ALVEOLAR o Dipalmithylphosphatidcholine/
Sleep (REPEAT) STAGE phosphatidylinositol/ phosphatidylglycerol
• Central Sleep Apnea – abnormality with the respiratory (Week 36 - term &
o Lipophilic proteins: SP-A, SP-B, SP-C
beyond)
control in the CNS; breathing while sleeping is difficult, if • Steroid/ thyroid hormones
not impaired • Vaginal delivery is beneficial to the baby.

B. Central Hypoventilation (aka Ondine’s Curse)

• Very rare with the voluntary aspect of breathing is intact
but abnormalities in automaticity exist
• Can only breathe when awake
C. Periodic Breathing & Cheyne-Stoke’s Ventilation
• Common in babies (physiological)
• After a period of apnea ® tidal volume and respiratory
frequency increase progressively after several breaths ®
frequency decreases ® normal breathing occurs
• Cheyne-Stoke’s – type of Periodic breathing; mechanism
not fully known; varying tidal volume; apnea ® tidal
volume and respiratory frequency increases ® apnea
again
D. Sudden Infant Death Syndrome
• Most common cause of death of infants during their first
year outside the perinatal period
• Abnormality in ventilation control; mechanism and cause
still unknown
• Possibility: failure to respond to increased CO2
• To avoid: keep baby in supine position and avoid loose
clothing
• Babies born during:
o Embryonic & Pseudoglandular Stage ® will not
survive
o Canalicular Stage ® may survive but with difficulty
o Saccular/ Terminal Stage: able to breathe but initially
labored
• Before delivery: constricted blood vessels; fluid in alveoli
CLINICAL SIGNIFICANCE
A. Respiratory Distress Syndrome (RDS I)
• also called Hyaline Membrane Disease
• Lack of or immature surfactant
• The more premature the baby is, the higher the chance
of RDS I after birth
• More toxic than type II because it has no surfactant
• Occurs during Saccular/ Terminal Stage
B. Respiratory Distress Syndrome II (Transient Tachypnea
of the Newborn)
• Very good surfactant level but delay in absorption of
fluids in lungs

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 FETAL CIRCULATION • Compensatory response: ­ with ventilation, oxygenation, and
• In utero, the baby is dependent on the placenta as the organ correction of acidosis along with vasodilation
of gas exchange, since air sacs are filled with fetal lung fluid
• High perfusion pressure, but low flow to the lungs E. Initiation of Breathing at Birth
o Only approximately 10% of the right ventricular output • Detected as early as 11-14 weeks of gestation
enters the pulmonary circulation of the fetus • By 34 weeks in utero – breathing pattern becomes regular
o Blood flow increases to 7% of cardiac output during the • The amount of time fetus spends breathing increases with
last trimester advancing gestational age
• During labor: fetal breathing activity ceases
Fetal Circulation • Different stimuli for initiation of respiration: Chemical,
Blood from umbilical cord ® IVC ® Right Atrium ® Right Ventricle Sensory, Thermal, Mechanical
® Pulmonary Artery ® Ductus Arteriosus ® Aorta ® Systemic
Circulation
• Pulmonary blood flow is diminished
• Arterioles are constricted
• Blood flow is shunted across ductus arteriosus instead of
going to the lungs
o Connects the pulmonary artery & aorta

Major changes taking place to switch to neonatal circulation:

• Intrauterine to extra-uterine life transition
• Lung’s epithelium: fluid secretion ® fluid excretion
• Distal lung units: 30 ml/kg fetal lung fluid
• Filled with inhaled air
• Blood flow increases about 20-fold
• At birth, it has to pick up a lot of oxygen for the expansion of
alveoli (lungs expand with air)
Figure 19. Initiation of respiration.
NEONATAL CIRCULATION
• Before delivery: constricted blood vessels; fluid in alveoli
• After delivery: Pulmonary arterioles dilate
o Oxygen enhances pulmonary arteriolar dilation
o Low oxygen ® pulmonary dilation will not occur
successfully ® ventilation-perfusion mismatch
o Oxygenation causes ductus arteriosus to constrict

CHANGES IN RESPIRATION

A. Normal Transition
• Major changes that take place within seconds after birth:
o Fluid in alveoli is reabsorbed
o Constriction of umbilical arteries and veins
o Lung tissue blood vessels dilate/ relax
B. Fetal Lung Clearance
• Squeezing effect: when baby passes through birth canal
resulting to an increase in pressure on thorax
• Absorbed by the epithelium ® drain to pulmonary vessels ®
drain to lymphatics
• Facilitated with effective initial breaths with crying + shouting
• Irregular episodes of hypoxia trigger the release of cortisol
o Effect on the Fibroblast Pneumocyte Factor (FPF) ®
producing more Type II cells
• Impaired by:
o Shallow ineffective respiration
o Apnea at birth with no lung expansion
C. Mechanism of Changes in Circulation
• Inflation of lungs results to mechanical distention of vessels
® improvement in oxygenation level ® rise of PO2
® induction of granulocytes in lungs to release kinin
® lowers concentrations of Prostaglandin E2
® closing of ductus arteriosus
• PGE2 maintains patency of ductus arteriosus
D. Pulmonary Blood Flow
• ¯ pulmonary blood flow with hypoxemia and acidosis due to
vasoconstriction.
o Thus, vasodilation must occur at birth to ­ pulmonary
blood low
Figure 20. Establishment of respiration.
F. Factors for Adequate Oxygenation
1. Mechanical events
o Initial chest compression ® expulsion of 1/3 pulmonary
fluid
o Subsequent events cause absorption of remaining fluids
o Once fully absorbed ® ¯ pulmonary vascular resistance
® ­ pulmonary & lymphatic circulation ® promotion of
adequate oxygenation
2. Air Entry into the lungs
o Once air enters the lungs ® ¯ alveolar surface tension
from surfactants ® ¯ interstitial pressure ® ­ pulmonary
vascular volume ® ­ pulmonary & lymphatic circulation
® promotion of adequate oxygenation
G. Establishment of Functional Residual Capacity (FRC)
• FRC is formed following the first breath
• Expiration is active for the first few breaths:
o To aid in distribution of ventilation
o To further clear pulmonary fluid from lungs
• Following vaginal delivery:
o FRC is usually formed by 2 hours
o Lung compliance increases more slowly over first 24
hours as pulmonary fluid is gradually reabsorbed

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 FACTORS OPPOSING FIRST BREATH D. Pulmonary Vessels
a) Alveolar surface tension • Increase in number of arteries in the acinus
b) Viscosity of lung fluid • Same degree of muscularity of arteries as seen in adults
c) Degree of lung compliance ® able to contract and perform bronchospasms
d) Mucus, blood, meconium, amniotic fluid • Increase responsiveness to acute hypoxia with
e) High negative inspiratory pressure is required to overcome: increasing age
o High flow resistance
o Inertia of liquid in the airways E. Infant Lungs
o Surface tension at the air-liquid interface
• Compliance
NORMAL CHANGES AT BIRTH o Small in infants: 4.75 ml/cm H2O
o Adults: 125 ml/cm H2O
• Fluid should go out
• Volume
• Blood vessels should dilate in the lungs
o Newborn (3 kg): 160 mL
• Air should enter the alveoli
o Adult: Male – 6 L; Female – 4.2 L
• Fluid should be reabsorbed
• Hyper-Reactive to Chronic Hypoxia
o If not achieved, may result in neonatal depression or
asphyxia
AIRWAY REACTIVITY
AGE-SPECIFIC RESPIRATORY PATHOGENS • Infants and children: more reactive airway to methylcholine
& histamine
• In Utero: **mnemonic: TORCH**
o Toxoplasmosis • Lower inspiratory flow rates than adults
o Other agents (syphilis, varicella, parvovirus B19) • Entrain less air to dilute nebulizer output = higher dose than
o Rubella older children
o Cytomegalovirus • In children, airway wall is 30% of the airway area compared to
o Herpes 15% in adults.
• At birth: Group B Strep/Chlamydia
- END -
• Infancy: H Influenza/Parainfluenza (2 years old)
• School-Aged Children: RSV (5 years old)

POST-NATAL LUNG GROWTH

• Continues in adolescent years and beyond
• Overall increased in dimensions:
o Tracheal diameter: 3x
o Alveolar dimensions: 4x
o Alveolar numbers = 10x
o Body mass = 20x
o Alveoli: 20-200 million by age 3
• Smoking results in a loss of about 50 million alveoli

ALVEOLARIZATION
• Terminal to respiratory bronchioles
• Coincides with new blood vessels formation
• Alveolar : arterial ratio
o Newborn – 20:1
o 2 years old – 12:1
o older child: 8-10:1
• 50 million alveoli at birth; 300 million alveoli in adults
RESPIRATORY STRUCTURES

A. Chest Wall
• Compliant (not too much, but not too little; just right)
• 3x greater than lung compliance
• Not as firm as adults

B. Ribs
• Infants: oriented in horizontal plane – slant in caudal
direction ® limited expansion of thoracic cage
• 10 years old: Downward slope of ribs seen in adults
• Rib compliance allows for deformation of the chest 2021C [PHY] LE 2 Finals Reviewer Groups
through the birth canal and easier expulsion of liquid from Trans Group - Widiyatno, Vidy
lungs before first breath 31 - Yap, Sean
• 25 years old: Ossification of sternum and vertebrae - Yaranon, Arianna
begins in utero - Ytienza, Sophia
- Yu, Airees
C. Airway Trans Group - Yu, Vincent
• High number of mucous glands compared to rate of 32 - Zamudio, Marielle
tracheal mucociliary clearance ® prone to develop colds - Zapanta, Jake
and coughs - Zhang, Eljine
• Airways behave as asthmatic lungs - Zipagan, Zakhira
o Usually disappear around 7 years old Editor - Rogacion, Jara
• Increase in amount of cartilage

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