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Pathogenesis of Veterinary Disease

Pathogenesis of Veterinary Disease

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Published by Andrew Richard
Point-form notes of pathogenesis of veterinary diseases, organized by body system
Point-form notes of pathogenesis of veterinary diseases, organized by body system

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Categories:Types, Research, Science
Published by: Andrew Richard on Aug 30, 2010
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06/01/2013

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Pathogenesis of Veterinary DiseaseGeneralIcterus
Prehepatic
- increased production of circulating bilirubin d/t lysis of erythrocytes
Hepatic
- impaired scavenging/processing of bilirubin d/t hepatocellular insufficiency
Posthepatic
- impaired excretion of bilirubin d/t biliary diseaseMechanisms of neoplastictransformation
Mesothelioma
: 1) direct irritation by asbestos, 2) disruption of mitotic spindle by asbestos fibres-aneuploidy,chromosomal damage, 3) generation of iron-dependent ROS; 4) induces MAPK and ERK-1/2 signaling - stimulationof c-Jun and AP-1 protooncogenes 
Growth advantage - produce/respond to many growth factors (PDGF-A/B, EGF, TGF-B); may have abnormalWnt/Frizzled pathway signalling 
Immortalization - telomerase activity increased in 90% of mesotheliomas 
Absence of Tumor Suppressor Genes - loss of p14, p16 (involved in P53/Rb signaling); loss of NF2-merlin 
Apoptotic Avoidance - increased expression of antiapoptotic Bcl-xL 
Angiogenesis - produce VEGF 
Matrix interactions - express collagens, matrix metalloproteinasesCarney ComplexProtein kinase A regulator gene (PKRAR1A) mutation???Amyloidosis
Reactive Amyloidosis
- Chronic inflammation > release of IL1& 6 by macrophages > synthesis of SAA byhepatocytes > limited proteolysis > amyloid deposited as β-pleated sheets in glomeruli, interstitium and/ortubular basement membrane > protein leakage through damaged glomeruli > proteinuria. Type I HypersensitivityProduction of IgE antibody → immediate release of vasoactive amines and other mediators from mast cells;recruitment of inflammatory cells (late-phase reaction) Type II HypersensitivityProduction of IgG, IgM → binds to antigen on target cell or tissue → phagocytosis or lysis of target cell by activatedcomplement or Fc receptors; recruitment of leukocytes Type III HypersensitivityDeposition of antigen-antibody complexes → complement activation → recruitment of leukocytes by complementproducts and Fc receptors → release of enzymes and other toxic molecules Type IV HypersensitivityActivated T lymphocytes → i) release of cytokines and macrophage activation; ii) T cell-mediated cytotoxicity Th1 responsesT-helper-1 (T
H
1) subset
synthesizes and secretes IL-2 and interferon-γ (IFN-γ) but not IL-4 or IL-5
delayedhypersensitivity, macrophage activation, and synthesis of opsonizing and complement-fixing antibodies, such asIgG2a in mice, all of which are actions of IFN-γ Th2 responses T
H
2 cells produce IL-4, IL-5 and IL-13 but not IL-2 or IFN-γ
synthesis of other classes of antibodies, notably IgE(mediated by IL-4 and IL-13), activation of eosinophils (mediated by IL-5)HaptenizationAdsorption of a small, nonimmunogenic molecule to a large carrier molecule (such as a protein) to produce animmunogenic complex, inducing an immune responseAcquired Melanosis (pigs) - ingestion of acorns by genetically predisposed pigs
swine tyrosinase acts on phenolic substances found inacorns
increase the biosynthesis and
 
the anomalous storage of melanin?Cancer BiologyCachexiaParaneoplastic hypercalcemiaectopic production of Parathyroid-related protein (PTH-rP) - mobilization of Acute Tumor Lysis syndrome inmicerapid and widespread lysis of tumor cells
massive release of intracellular components such as nucleic acids,potassium, and phosphorus
disseminated microemboli composed of nuclear and cytoplasmic debris derivedfrom lysed tumor cells
mechanical obstruction of capillary beds
deathMechanisms of viral malignanttransformation
Subgroup J Avian Leukosis virus
 
– associated histiocytic sarcoma
– in ovo/neonatal infection
persistentviremia
ChL5 (myelomonocytic cells and activated T Lymphocytes), CD45 (hematopoietic except erythoid,platelets),
 
and MHC class II – positive tumors arising from splenic ellipsoids and
 
red pulp
metastasis to liver,kidney, and other organs
Equine Sarcoid
– Bovine Papillomaviruses 1/2 express E5 major transforming oncoprotein
binds PDGF-BR
activating PI3K-AKT-cyclinD pathway
proliferation ; also activation of activation of phosphor-JNK and phosphor- JUNSelf-sufficiency in growthsignals (Oncogenes) Tumors have the capacity to proliferate without external stimuli, usually as a consequence of oncogene activation- protooncogenes - constitutively expressed
 
oncoproteins endow cell with self-sufficiency in growth
 
Growth Factors (PDGF-B/SIS; FGF/HST-1; INT-1; TGF-B/TGF-a; HGF) 
Growth Factor Receptors (EGF-R family/ERB-1/2; CSF-1R/FMS; neurotropic factors receptor/RET; PDGFR; stemcell factor receptor/KIT) 
Proteins involved in Signal Transduction (GTP-binding proteins/K-RAS, HRAS, N-RAS; nonreceptor tyrosinekinase/ABL; Ras signal transduction/BRAF; WNT signal transduction/B-catenin) 
nuclear regulatory proteins (C-MYC, N-MYC, L-MYC) 
cell cycle regulators (cyclins/cyclin-D, cyclin-E; cyclin-dependent kinase/CDK4)Insensitivity to growth-inhibitory signals (tumorsuppressor genes) Tumors may not respond to molecules that are inhibitory to the proliferation of normal cells such as transforminggrowth factor-β (TGF-β), and direct inhibitors of cyclin-dependent kinases.- TGF-βreceptor, E-cadherin SMAD 2 and SMAD 4
Growth inhibition, Cell adhesionFailure of TGF-B signalling (inactive TGF-B receptor, diminished SMAD-2/4)
diminished CDK inhibitors(Cip/Kip, INK4a)
uncontrolled CDK4 complex formation
failure of brake mechanisms on cell cycleprogression from G1/S(diminished B-catenin expression
) Diminished E-cadherin expression
disaggregation of cells- NF-1
Inhibition of RAS signal transduction and of p21 cell-cycle inhibitorLoss of NF-1
diminished neurofibromin
uncontrolled RAS-GTP binding and activation
continuous cellproliferation signalling- NF-2
Cytoskeletal stabilityLoss of NF-2
diminished merlin
diminished actin-CD44 binding
unstable cell-matrix interactions
abnormal contact inhibition- APC/ β-catenin
Inhibition of signal transductionDiminished APC
failure of downregulation of B-catenin, increased translocation to nucleus
forms
 
complex with TCF
upregulation of cMYC, cyclin D1, etc
upregulated cell proliferationAltered B-catenin - E-cadherin interaction
altered cell adhesiveness- PTEN
PI-3 kinase signal transductionDiminished PTEN activity
diminished transcription of p27 Kip/Kip cell-cycle inhibitor and stabilizing protein
uncontrolled CDK4 complex formation
failure of brake mechanisms on cell cycle progression from G1/S- RB
Regulation of cell cycleRB mutation (knock-out or abnormal E2F binding site)
failure of transcription of E2F transcription factors
 uncontrolled CDK4 complex formation
failure of brake mechanisms on cell cycle progression from G1/S- p53
Cell-cycle arrest and apoptosis in response to DNA damage- Failure of p53 signalling
diminished CDK inhibitors (Cip/Kip, INK4a)
uncontrolled CDK4 complexformation
failure of brake mechanisms on cell cycle progression from G1/S- DNA damage
DNA-dependent protein kinase and
 ATM
(ataxia-telangectasia mutated) activation
lackof phosphorylation of p53 and protein unfolding
unable able to bind to DNA
fails to stimulatetranscription of several genes that mediate cell-cycle arrest and apoptosis- WT-1 p16(INK4a)
Nuclear transcription; Regulation of cell cycle by inhibition of cyclin-dependent kinasesDiminished p16(Ink4a) activity
lost capacity to block cyclin D-CDK4 activity and to prevent RBphosphorylation during the cell cycle- BRCA-1 and BRCA-2
DNA repair- KLF6
Transcription factorDiminished KLF6
decreased transcription of Cip/Kip cell-cycle inhibitor p21Evasion of apoptosisTumors may be resistant to programmed cell death, as a consequence of inactivation o
 p53
or other changes- BCL-2Overexpression of BCL-2
accentuated protection from mitochondrial pathway of apoptosis- P53Diminished expression of p53
diminished transcription of proapoptotic genes (BAX, BID)Defects in DNA repairTumors may fail to repair DNA damage caused by carcinogens or unregulated cellular proliferation- DNA mismatch Repair Abnormalities: MSH2(2p16),
MLH1
(3p21) genesFailure of nucleotide mismatch repair
progressive accumulation of abnormalities in various genes(protooncogenes, TSGs)
microsatellite instability- nucleotide excision repair – failure of repair of pyrimidine crosslinks
impaired DNA replication- recombination repair- ATM geneDiminished expression of ATM (ataxia-telangiectasis) gene
impaired dectection of DNA double-strandbreaks (ionizing radiation, O2 free radicals)
diminished phosphorylation of p53
failure of cell cycle arrestand apoptosis- BRCA genes (BRCA-1/2)Diminished BRCA-1/2 expression
diminished RAD51 binding
impaired repair of double-strand DNAbreaks, chromatin remodellingLimitless replicative potential – Telomerase Tumor cells have unrestricted proliferative capacity, associated with maintenance of telomere length and functionEnhanced telomerase expression
loss of normal telomere shortening with cell replication
failure of telomere-mediated, p53-dependent proliferative arrest/apoptosisSustained angiogenesisTumors are not able to grow without formation of a vascular supply, which is induced by various factors, the mostimportant being vascular endothelial growth factor (VEGF)- production of angiogenic factors (HIF-1a-mediated expression of VEGF)- loss of angiogenesis inhibitors – mutation of p53
diminished thrombospondin-1 expression, accentuatedVEGF, HIF-1aMechanisms of metastasis/invasion Tumor metastases are the cause of the vast majority of cancer deaths and depend on processes that are intrinsicto the cell or are initiated by signals from the tissue environment1) Invasion of Extracellular Matrix: detachment of cells from one another- (diminished catenin expression
) - downregulation of E-cadherin
diminished homotypic adhesions betweencells2) attachment ot matrix components- Atypical expression/distribution of laminin and fibronectin receptors, increased/atypical expression of integrins
invasion of basement membrane, attachment to ECM components3) degradation of ECM- abnormal/enhanced expression of serine, cysteine, matrix metaloproteinases (particularly Type IV collagenasesMMP2, MMP9)- matrix degradation releases growth promoting, angiogenic/antiangiogenic, chemotactic factors4) migration of tumor cells5) Vascular dissemination and homing of tumor cells- homotypic adhesions between tumor cells, heterotypic adhesions with platelets (promotes survival andimplantability)- Degradation of ECM (as above)- CD44 expression (a normal Tcell adhesion molecule used to migrate to selective sites through interactions withhigh endothelial venules) – expression may favour metastasis- tumor metastasis homing mediated by:
 
- adhesion molecule-ligand interactions in endothelium of target tissues- chemokine receptor expression on tumor cells – homing to tissues in which chemokine ligand is expressedSialyl-Le
a
– E-selectin ligand - T and Tn antigens -Cyclooxygenase activity incancerAlimentaryPalatoschisis (Cleft Palate)genetic abnormalities (inherited?); excessive administration of Vit A during gestation (dogs); administration ocortisone during gestation (Dogs) --> Failure of fusion of lateral palatine processes --> Aspiration pneumonia,emaciationCheiloschisis (Hare Lip)Failure of fusion of maxillae along midline (philtrum) --> Aspiration pneumonia, emaciationOdontomahamartoma of enamel organ --> mix of fully-differentiated dental components: Complex - do not form dentalstructures; Compound - form numerous differentiated but abnormal dental structures ("denticles")Dentigerous Cystdental dysgenesis - abnormal proliferation of cell rests of Malassez --> epithelial-lined cyst; may containrudimentary/malformed teeth --> may become impacted with keratin; may cause fistula formationDiarrheafour major mechanisms by which diarrhea may occur:1)
Malabsorption
with or without bacterial fermentation
osmotic diarrhea. Generally, this is a problem of thesmall intestine, but secondary colonic malfunctions can occur because of malabsorption of bile salts and fattyacids that stimulate fluid secretion in the large intestine.
2) Hypersecretion
by a structurally intact mucosa. This activity results in a net efflux of fluid and electrolytesindependent of permeability changes, absorptive capacity, or exogenously generated osmotic gradients.3)
Exudation
caused by increased capillary or epithelial permeability (protein-losing enteropathy).4)
Hypermotility
(increased rate, intensity, or frequency of peristalsis)
decreased mucosal contact time,digestion and absorption of nutrients should be less efficient
decreased motility in some diseases allows forincreased bacterial proliferation; some enterotoxins can stimulate intestinal motilitySegmentalintestinal/colonic/anal aplasia(Atresia coli/ani)- segmental ischemia- peritonitis- failure of development of luminal epithelial primordiumMeckel's Diverticulum - retention of stalk of yolk sac
omphalomesenteric duct remnant (blind-ended sac near termination of ileum)Colonic Aganglionosis (LethalWhite Foal Syndrome)White patterned horses (esp. vero foals). Ile118Lys endothelin receptor B (EDNRB) mutation --> failure of migration of neuroblasts from neural crest - congenital lack of myenteric and/or submucosal plexuses in distalcolon/anus - contracted/nonperistaltic distal colon - proximal megacolon (Model for the Hirschprung aganglionosisof humans).Equine Dysautonomia (GrassSickness)Unknown pasture toxin > Toxic intestinal ganglion cell necrosis > progressive craniocaudal impaction. Seasonal.Hares also affected.Mycotic RumenitisGrain overload > rumenal acidosis > mucosal damage > opportunistic fungal inf > vasculitis > ischemia &mucosal ulcerationRumenal Tympany (Bloat)
Bloat, Primary or frothy
- ingestion of legumes > stable foam formation > foam obstructs cardia and inhibitsnormal eructation > rumenal distention > respiratory distress > death from anoxia
Bloat, Secondary
- Failure of eructation (vagal indigestion) > distention of rumen > respiratory distress > deathdue to anoxia
Bloat line
- Bloat > elevated intra thoracic pressure > decreased venous return (passive congestion) > cyanosisof extra-thoracic (cervical) esophageal mucosa and pallor of intra-thoracic esophageal mucosaMCT-associated duodenalulcerationMast Cell Tumor somewhere in body > histamine release > ↑ gastric parietal cell HCl secretion > pyloric mucosaldamage & ulcerationCardiovascularVitamin D-related metastaticmineralizationChronic granulomatous disease (M. avium paratuberculosis) - Macrophages Produce Vit D Analog > AorticMineralizationAtherosclerosisHypothyroidism or DM > lipoprotein lipase activity > cholesterol > atherosclerosisScurvyGuinea pig, P, red-vented bulbul bird, northern shrike, Indian pipstrels, channel catfish, & primates normally lackL-Gulonolactone Oxidase necessary for Vit C synthesisPathogenesis: Lack L-Gulonolactone Oxidase > dietary Vit C defic > ↓ lysine & proline hydroxylation > impaired Type 1 & 4 collagen synthesis > weakened vessel walls (physeal cartilage deformity) > periarticular hemorrhage(&/or osteochondrodysplasia)Ionophore ToxicosisToxic exposure to Lasalocid/Monensin > Exchange of cations for protons across cell membranes without using ionchannels > decreased ATP production, increased ATP utilization (to maintain cation concentrations) > cell death >Myocardium necrosis and fibrosisE. coli-associated EdemaDiseaseEdema of Eyelids, Mesocolon, Gallbladder, Glandular Portion of Stomach, Mesenteric LNs, Larynx, & Lungs;Hydrothorax & Hydropericardium; Bilaterally Symmetric Brainstem MalaciaE. coli Inf > Shiga-like toxin prod > endothelial damage > ↑ vascular permeability > edema (various tissues)In brain: Shiga like toxin type IIe > Necrosis of smooth muscle cells in the arteriole and arteries > vascularcompromise > infarctionFibrinosuppurative pericarditis
Traumatic Reticuloperitonitis/Pericarditis (Hardware Dz)
- Ingest wire foreign body > penetrates reticulumwall & diaphragm into pericardium > fibrinous pericarditis & epicarditisHigh-Altitude DiseaseHigh altitude > chronic hypoxia > pulmonary artery vasoconstriction > right ventricular hypertrophy & failure >chronic passive congestion > edemaViral Vascular Disease
Bluetongue
- Culicoides (midge, gnat) bites sheep > hematopoietic cell viral replication > viremia > widespreadendothelial cell viral replication & damage > hemorrhage, edema, thrombosis, & infarction - Hemorrhage at theBase of the Pulmonary Artery; Rumenal Pillar Hemorrhage & Necrosis
Non-effusive FIP
- Coronaviral inf of møs > weak cell-mediated immune response > virus persists in møs >pyogranulomatous inflam (non-effusive form) Type III HypersensitivityVasculitis
Purpura Hemorhagica
- Streptococcus equi equi Ag/Ab complexes. Ag/ab complex vasculitis.
Aleutian Mink Disease
- Parvoviral inf of lymphocytes >viral release > immune complex deposition in vessels,

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