Conserved Fibrotic Response Module

Module fibrotic_response 11 disorders Pathograph 5

A conserved pathological module representing the dysregulation of normal wound healing (GO:0042060) that underlies organ fibrosis across tissues. Tissue injury triggers inflammation and resident mesenchymal cell activation, leading to myofibroblast transdifferentiation, excessive extracellular matrix deposition, and progressive architectural distortion with organ dysfunction. This module captures the shared core of fibrotic disease across liver, lung, heart, kidney, skin, and other organs. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting organ-specific cell types and anatomical locations while preserving the conserved causal chain and signaling axes.

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Pathophysiology Nodes

5 shared nodes are defined in this module.

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Cell Types

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Biological Processes

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "fibrotic_response#Mesenchymal Cell Activation"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding cell types, biological processes, and causal edges, specialized to their organ context. Key organ-specific substitutions: liver uses hepatic stellate cells (CL:0000632), lung uses pulmonary fibroblasts, heart uses cardiac fibroblasts, kidney uses mesangial cells (CL:0000650) or pericytes.

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Used By Disorder Entries

Budd-Chiari Syndrome via Congestive Hepatic Fibrosis → Mesenchymal Cell Activation

Dupuytren Contracture via Fascial Microinjury and Aberrant Wound Healing → Tissue Injury , Profibrotic Signaling and Inflammatory Amplification → Inflammatory Recruitment and Amplification , Myofibroblast Activation and Contraction → Mesenchymal Cell Activation , Excessive Collagen Deposition and Cord Formation → Excessive ECM Deposition , Digital Flexion Contracture and Hand Dysfunction → Architectural Distortion and Organ Dysfunction

Eosinophilic Fasciitis via TGF-beta-Driven Fascial Fibroblast Activation → Mesenchymal Cell Activation

Hepatic Fibrinogen Storage Disease via Hepatic Stellate Cell Activation → Mesenchymal Cell Activation , Excessive Hepatic ECM Deposition → Excessive ECM Deposition

Hepatic veno-occlusive disease-immunodeficiency syndrome via Hepatic stellate cell activation and fibrotic remodeling → Mesenchymal Cell Activation , Progressive hepatic fibrosis and organ dysfunction → Excessive ECM Deposition

Idiopathic Pulmonary Fibrosis via Repetitive alveolar epithelial injury and aberrant repair → Tissue Injury , Profibrotic macrophage recruitment and amplification → Inflammatory Recruitment and Amplification , Fibroblast activation and myofibroblast differentiation → Mesenchymal Cell Activation , Excessive extracellular matrix deposition → Excessive ECM Deposition , Architectural distortion and gas-exchange failure → Architectural Distortion and Organ Dysfunction

IgG4-Related Disease via Storiform Fibrosis → Mesenchymal Cell Activation

Liver Cirrhosis via Hepatic Stellate Cell Activation → Mesenchymal Cell Activation

Sarcoidosis via Fibrotic Tissue Remodeling → Mesenchymal Cell Activation

Volumetric Muscle Loss via Frank Muscle Loss and Destruction of the Regenerative Niche → Tissue Injury , Persistent Open-Wound Inflammatory Stimulus → Inflammatory Recruitment and Amplification , Myofibroblast Activation and Excessive Collagen Deposition → Mesenchymal Cell Activation , Excessive ECM Deposition , Fibrotic Scar Replacement and Persistent Functional Deficit → Architectural Distortion and Organ Dysfunction

Wilson Disease via Hepatic Stellate Cell Activation → Mesenchymal Cell Activation , Excessive Hepatic ECM Deposition → Excessive ECM Deposition

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Pathograph

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Pathophysiology

Tissue Injury

trigger

Chronic or repeated injury to organ-specific parenchymal cells initiates the fibrotic cascade. The nature of injury varies by organ (viral hepatitis in liver, inhaled particles in lung, ischemia in heart, immune complex deposition in kidney) but the downstream response converges on a common inflammatory and reparative program.

Wound Healing GO:0042060 DYSREGULATED

Used by disorders

Dupuytren Contracture as Fascial Microinjury and Aberrant Wound Healing

Idiopathic Pulmonary Fibrosis as Repetitive alveolar epithelial injury and aberrant repair

Volumetric Muscle Loss as Frank Muscle Loss and Destruction of the Regenerative Niche

Downstream

Inflammatory Recruitment and Amplification

Inflammatory Recruitment and Amplification

amplifier

Damage-associated molecular patterns (DAMPs) from injured parenchymal cells recruit and activate macrophages, which produce pro-fibrotic cytokines including TGF-beta, PDGF, and IL-13. This inflammatory phase bridges tissue injury to mesenchymal cell activation and is a key amplification step in the fibrotic cascade.

Macrophage CL:0000235

Inflammatory Response GO:0006954 INCREASED Leukocyte Migration GO:0050900 INCREASED

Used by disorders

Dupuytren Contracture as Profibrotic Signaling and Inflammatory Amplification

Idiopathic Pulmonary Fibrosis as Profibrotic macrophage recruitment and amplification

Volumetric Muscle Loss as Persistent Open-Wound Inflammatory Stimulus

Downstream

Mesenchymal Cell Activation

Mesenchymal Cell Activation

central effector

Resident mesenchymal cells (fibroblasts, hepatic stellate cells, pericytes, or mesangial cells depending on organ) are activated by TGF-beta and other pro-fibrotic signals to transdifferentiate into alpha-SMA-positive myofibroblasts. This is the central effector step of fibrosis, conserved across all organs. The specific precursor cell type varies by tissue but the TGF-beta/Smad signaling axis driving activation is shared.

Fibroblast CL:0000057 Myofibroblast CL:0000186

TGF-beta Receptor Signaling GO:0007179 INCREASED

Used by disorders

Budd-Chiari Syndrome as Congestive Hepatic Fibrosis

Dupuytren Contracture as Myofibroblast Activation and Contraction

Eosinophilic Fasciitis as TGF-beta-Driven Fascial Fibroblast Activation

Hepatic Fibrinogen Storage Disease as Hepatic Stellate Cell Activation

Hepatic veno-occlusive disease-immunodeficiency syndrome as Hepatic stellate cell activation and fibrotic remodeling

Idiopathic Pulmonary Fibrosis as Fibroblast activation and myofibroblast differentiation

IgG4-Related Disease as Storiform Fibrosis

Liver Cirrhosis as Hepatic Stellate Cell Activation

Sarcoidosis as Fibrotic Tissue Remodeling

Volumetric Muscle Loss as Myofibroblast Activation and Excessive Collagen Deposition

Wilson Disease as Hepatic Stellate Cell Activation

Downstream

Excessive ECM Deposition

Excessive ECM Deposition

effector

Activated myofibroblasts produce excessive collagen (types I and III) and other extracellular matrix proteins while also secreting tissue inhibitors of metalloproteinases (TIMPs) that block matrix degradation. The imbalance between ECM production and degradation leads to progressive matrix accumulation. This process is conserved across organs though the specific collagen subtypes and matrix composition may vary.

Myofibroblast CL:0000186

ECM Organization GO:0030198 INCREASED Collagen Biosynthesis GO:0032964 INCREASED Collagen Fibril Organization GO:0030199 INCREASED

Used by disorders

Dupuytren Contracture as Excessive Collagen Deposition and Cord Formation

Hepatic Fibrinogen Storage Disease as Excessive Hepatic ECM Deposition

Hepatic veno-occlusive disease-immunodeficiency syndrome as Progressive hepatic fibrosis and organ dysfunction

Idiopathic Pulmonary Fibrosis as Excessive extracellular matrix deposition

Volumetric Muscle Loss

Wilson Disease as Excessive Hepatic ECM Deposition

Downstream

Architectural Distortion and Organ Dysfunction

Architectural Distortion and Organ Dysfunction

consequence

Progressive matrix accumulation distorts normal tissue architecture, leading to organ-specific structural changes: nodular regeneration and portal hypertension in liver, honeycombing in lung, interstitial expansion and stiffening in heart, glomerulosclerosis in kidney. The end result is irreversible loss of organ function. While the specific architectural consequences are organ-dependent, the underlying process of progressive structural distortion from excessive matrix is conserved.

Used by disorders

Dupuytren Contracture as Digital Flexion Contracture and Hand Dysfunction

Idiopathic Pulmonary Fibrosis as Architectural distortion and gas-exchange failure

Volumetric Muscle Loss as Fibrotic Scar Replacement and Persistent Functional Deficit