Beyond TGF-β/MMP
Advanced Pathophysiology in Fibrosis & Chronic Wound Healing
Expanding the Pathophysiological Paradigm
Fibrosis and chronic non-healing wounds extend far beyond dysregulated TGF-β/MMP signaling. Our research identifies five critical independent factors driving pathological tissue remodeling.
Factor 1: Fibrin Network Persistence
Early Inflammatory Role
Forms provisional matrix for cell migration and acts as scaffold for fibroblast infiltration.
Pathological Implications
- • Fibrinolytic deficiency impairs degradation
- • Factor XIIIa crosslinking increases stiffness
- • Enhanced fibroblast activation
Factor 2: Microbial Load & Biofilms
Bacterial Persistence
Biofilms (S. aureus, P. aeruginosa) resist phagocytosis, sustaining M1 polarization.
Additional Pathogens
- • Hepatitis C → liver fibrosis via oxidative stress
- • Chronic Candida → non-healing ulcers
Factor 3: Defective Clearance
Impaired Efferocytosis
Macrophage dysfunction (diabetes) fails to clear apoptotic cells.
"Fibrin Traps" Phenomenon
Fibrin entraps inflammatory cells forming pro-inflammatory nidus, evolving into hyalinized scar tissue.
Factor 4: Hypoxia & Oxidative Stress
Ischemia-Reperfusion Injury
ROS generation promotes ECM crosslinking and matrix stiffening.
HIF-1α Stabilization
Drives VEGF expression but paradoxically promotes fibrosis in chronic hypoxia.
Factor 5: Biomechanical Factors
Tissue Stiffness Sensing
Fibroblasts sense matrix rigidity via integrin-ROCK pathway.
Vascular Shear Stress
Altered flow patterns cause endothelial dysfunction, promoting TGF-β release.
Why Does Fibrin Network Persist?
Defective Fibrinolysis
- • Decreased plasminogen activation
- • PAI-1 overexpression in diabetes/obesity
- • α2-antiplasmin inhibition
Macrophage Clearance Failure
Unlike cellular debris, fibrin requires plasmin-mediated dissolution. When plasmin activity is inhibited, fibrin becomes a persistent inflammatory scaffold.
Therapeutic Targets
| Target | Approach | Example |
|---|---|---|
| Fibrinolysis | Recombinant tPA | Alteplase for chronic wounds |
| Biofilm | Antibiotic hydrogels | Vancomycin-eluting dressings |
| Efferocytosis | Annexin A1 mimetics | Resolvin E1 trials |
| Oxidative Stress | Nrf2 activators | Bardoxolone methyl |
Key Research Insights
🔬 Independent Pathways
Fibrin density, infection, hypoxia, and macrophage dysfunction operate beyond TGF-β/MMP mechanisms.
🧬 Inflammatory Scaffold
Uncleared fibrin acts as pro-inflammatory scaffold perpetuating fibrotic responses.
⚡ Mechanical Integration
Biofilms and mechanical stress create positive feedback loops maintaining non-healing states.
💊 Multimodal Therapy
Effective treatments require combined fibrinolysis, infection control, and macrophage reprogramming.