Jeremy Aditya FG4

Pathophysiology
QBD 1

2306253272
What is wound healing?
The capacity of the tissue to heal the
damage resulting from toxic injuries and
inflammation. Two reaction: regeneration
and scar formation

Regeneration:
Proliferation of surviving cells
Driven by signals from growth
factors and extracellular matrix
Tissue returns to normal state
Scar formation:
Damage is severe
repair by layering connective
(fibrous) tissue.
.Kumar V, Abbas AK, Aster JC, Perkins JA, Robbins SL. Robbins basic pathology. 9th ed. Philadelphia, Pa Elsevier, Saunders; 2013.
Wallace HA, Zito PM, Basehore BM. Wound Healing Phases [Internet]. Nih.gov. StatPearls Publishing; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470443/
Mechanism of Tissue Regeneration
In epithelieal tissues:
Growth factor produced by macrophages at damaged site and
residual epithelial cells
Growth factors bind to ECM protein
Activates signaling pathway --> changes gene expression -->
tissue stem cells to mature
New cells migrate to damaged site to restore the tissue
ex Skin, lining of intestine

In parenchymal organs:
Pancreas, adrenal, thyroid, and lung
Hypertrophy and hyperplasia of remaining
cells
Production of GF and interaction with ECM
.Kumar V, Abbas AK, Aster JC, Perkins JA, Robbins SL. Robbins basic pathology. 9th ed. Philadelphia, Pa Elsevier, Saunders; 2013.
Wallace HA, Zito PM, Basehore BM. Wound Healing Phases [Internet]. Nih.gov. StatPearls Publishing; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470443/
General Steps of scar development
1. Formation of platelets plug to stop bleeding and
provide scaffold for inflammatory cells
2. Inflammation. Chemokines from mature platelets
brings neutrophils and monocyte to injured site.
3. M1 Macrophage clears microbes. M2 macrophage
produce growth factor --> cell proliferation.
4. Cell proliferation. Epithelial cells, endothelial and
other vascular cells, and fibroblasts, proliferate and
migrate to injured site. Forming granulation tissue
5. Remodelling. Fibroblasts is reorganized to produce
stable fibrous scar. Deposition of collagen. 2-3
weeks after injury
.Kumar V, Abbas AK, Aster JC, Perkins JA, Robbins SL. Robbins basic pathology. 9th ed. Philadelphia, Pa Elsevier, Saunders; 2013.
Wallace HA, Zito PM, Basehore BM. Wound Healing Phases [Internet]. Nih.gov. StatPearls Publishing; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470443/
Angiogenesis
New blood vessels development from
existing vessels

1. Vasodilation. In response to NO and VEGF

2. Formation of vessel sprout, pericyte
detachment from basement membrane
3. Migration of endothelial cells
4. Proliferation of endothelial cells behind
the tip
5. Remodeling into capillary tubes
6. Periendothelial cells recruitment to form
mature vessels

.Kumar V, Abbas AK, Aster JC, Perkins JA, Robbins SL. Robbins basic pathology. 9th ed. Philadelphia, Pa Elsevier, Saunders; 2013.
2Wallace HA, Zito PM, Basehore BM. Wound Healing Phases [Internet]. Nih.gov. StatPearls Publishing; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470443/
 Growth factors in wound healing
VEGF :
Migration and proliferation of endothelial cells
Promotes vasodilation by producing NO
FGF (Fibroblast growth factors):
Proliferation of endothelial cells.
Promote inflammation by inflammatory cells
PDGF (Platelet derived growth factor)
Chemotactic for inflammatory cells
Proliferation of fibroblasts, endothelial cells
ECM protein synthesis
TGF-β (produced by granulation tissue)
Inhibit inflammatory response
Synthesis and deposition of collagen and fibronectin
Increases fibrosis
Decrease degradation of ECM proteins
.Kumar V, Abbas AK, Aster JC, Perkins JA, Robbins SL. Robbins basic pathology. 9th ed. Philadelphia, Pa Elsevier, Saunders; 2013.
Wallace HA, Zito PM, Basehore BM. Wound Healing Phases [Internet]. Nih.gov. StatPearls Publishing; 2019. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470443/
Growth factors in wound healing

.Kumar V, Abbas AK, Aster JC, Perkins JA, Robbins SL. Robbins basic pathology. 9th ed. Philadelphia, Pa Elsevier, Saunders; 2013.
Factors impairing wound healing
1. Oxygenation
a. Needed to sustain the healing process
2. Infection
a. Prolonged inflammation due to infection
3. Age
a. delayed T-cell infiltration
b. alterations in chemokine production
c. reduced macrophage phagocytic capacity
4. Stress
a. Reduces the levels of the pro-inflammatory cytokines
5. Diabetes
a. hypoxia .Kumar V, Abbas AK, Aster JC,
Perkins JA, Robbins SL. Robbins

b. dysfunction in fibroblasts and epidermal cells basic pathology.

Philadelphia, Pa
9th ed.
Elsevier,

6. Medications
Saunders; 2013.
Wallace HA, Zito PM, Basehore
BM. Wound Healing Phases

a. interfere with clot formation or platelet function [Internet]. Nih.gov. StatPearls

Publishing; 2019. Available from:

b. ex: Glucocorticoid Steroids

https://www.ncbi.nlm.nih.gov/bo
oks/NBK470443/
 Impaired wound healing
1. Venous leg ulcers
a. Due to chronic venous hypertension
b. Red cell breakdown
c. Wounds do not heal due to poor delivery of
oxygen
2. Arterial Ulcers
a. Due to atherosclerosis of peripheral arteries
b. Associated with diabetes
c. Ischemia causes atrophy and necrosis
3. Pressure sores
a. Prolonged compression of tissues against a
bone
b. Immobile elderly with morbidities
4. Diabetic ulcers
a. Due to small vessel disease
Kumar V, Abbas AK, Aster JC, Perkins JA, Robbins SL. Robbins basic pathology. 9th ed. Philadelphia, Pa Elsevier, Saunders; 2013.
Pathophysiology of vignette
Vignette Summary:

58-years old male

History of type-2 diabetes mellitus 8 yrs ago
Wound at the sole of foot
Wound has not healed since 3 months ago
Wound do to tripping on rock
Edge of wound is slightly raised
Wound appeared black
Wound omitting foul smell
Suspected diabetes ulcer
Pathophisiology of diabetic ulcers

Hyperglycemia produces oxidative stress on nerve

cells and leads to neuropathy. Due to increased
glucose metabolism-> overproduction of ROS

Neuropathy:
a. Motoric: foot deformities, skin ulceration
b. Autonomic: impaired gland functions-> dry
skin and skin breakdown
c. Sensory: decreased peripheral sensation -> no
feeling of wound-> more damage-> ulcers

1. Aumiller WD, Dollahite HA. Pathogenesis and management of diabetic foot ulcers. Journal of the American Academy of Physician Assistants [Internet]. 2015 May;28(5):28–34. Available from:
https://journals.lww.com/jaapa/fulltext/2015/05000/Pathogenesis_and_management_of_diabetic_foot.6.aspx
2. Guo S, DiPietro LA. Factors Affecting Wound Healing. Journal of Dental Research. 2020 Feb 5;89(3):219–29.
3. Patel S, Srivastava S, Singh MR, Singh D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomedicine & Pharmacotherapy. 2019
Apr;112(112):108615.
Pathophisiology of diabetic ulcers

Hyperglycemia causes vascular alterations:

Vasoconstriction and plasma hypercoagulation in
peripheral arteries
Leads to Atherosclerosis
Ischemia & lack of oxygenation -> Ulceration
Hyperglycemia causes epigenetic changes in
macrophage -> dysfunctional macrophage ->
disrupts wound healing

1. Aumiller WD, Dollahite HA. Pathogenesis and management of diabetic foot ulcers. Journal of the American Academy of Physician Assistants [Internet]. 2015 May;28(5):28–34. Available from:
https://journals.lww.com/jaapa/fulltext/2015/05000/Pathogenesis_and_management_of_diabetic_foot.6.aspx
2. Guo S, DiPietro LA. Factors Affecting Wound Healing. Journal of Dental Research. 2020 Feb 5;89(3):219–29.
3. Patel S, Srivastava S, Singh MR, Singh D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomedicine & Pharmacotherapy. 2019
Apr;112(112):108615.
 Pathophisiology of diabetic ulcers

Patel S, Srivastava S, Singh MR, Singh D. Mechanistic insight into diabetic wounds: Pathogenesis, molecular targets and treatment strategies to pace wound healing. Biomedicine & Pharmacotherapy. 2019
Apr;112(112):108615.