Conserved Fibrotic Response Module

Module fibrotic_response 6 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

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

Sarcoidosis via Fibrotic Tissue Remodeling → Mesenchymal Cell Activation

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 link DYSREGULATED

Used by disorders

Idiopathic Pulmonary Fibrosis as Repetitive alveolar epithelial injury and aberrant repair

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 link

Inflammatory Response link INCREASED Leukocyte Migration link INCREASED

Used by disorders

Idiopathic Pulmonary Fibrosis as Profibrotic macrophage recruitment and amplification

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 link Myofibroblast link

TGF-beta Receptor Signaling link INCREASED

Used by disorders

Budd-Chiari Syndrome as Congestive Hepatic Fibrosis

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

Sarcoidosis as Fibrotic Tissue Remodeling

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 link

ECM Organization link INCREASED Collagen Biosynthesis link INCREASED Collagen Fibril Organization link INCREASED

Used by disorders

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

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

Idiopathic Pulmonary Fibrosis as Architectural distortion and gas-exchange failure