Conserved Fibrotic Response Module

Module fibrotic_response 35 disorders Pathograph 6

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

Wound Healing GO:0042060 DYSREGULATED Inflammatory Response GO:0006954 INCREASED Leukocyte Migration GO:0050900 INCREASED TGF-beta Receptor Signaling GO:0007179 INCREASED ECM Organization GO:0030198 INCREASED Collagen Biosynthesis GO:0032964 INCREASED Collagen Fibril Organization GO:0030199 INCREASED

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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Experimental Models / Non-animal Systems

Scar-in-a-Jar macromolecular-crowding fibroblast fibrosis assay PRIMARY CELL CULTURE

A macromolecular-crowding culture system in which an inert crowder added to the medium excludes volume and thereby accelerates procollagen processing and extracellular deposition, producing a quantifiable collagen matrix in days rather than weeks. TGF-beta 1 is supplied to drive the fibroblast to myofibroblast transition, and the deposited matrix is read directly in the well by immunofluorescence or, in the prolonged variant, by neoepitope ELISAs on the supernatant. The collagen-producing cell type is a parameter of the assay rather than a fixed feature of it, which is what makes this a module-level rather than an organ-level model. The same platform has been run with embryonic and adult lung fibroblasts, embryonic and adult dermal fibroblasts, corneal keratocytes and vocal fold fibroblasts, so the two nodes it is linked to here are exercised without committing to an organ.

Models: Mesenchymal Cell Activation (recapitulates), Excessive ECM Deposition (recapitulates)

PMID:34028741

tissue_term is deliberately omitted. The assay has no tissue of its own: the fibroblast source is a parameter, and binding any one organ would assert a specificity the platform does not have. This is the property that licenses a module-level model here rather than the organ-specific lung chip and liver microtissue plate that prompted the gap (issue #9997).

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Used By Disorder Entries

Adenomyosis via Lesional Fibrosis and Myofibroblast Transdifferentiation → Mesenchymal Cell Activation

Alcohol-Associated Liver Disease via Hepatic Stellate Cell Activation → Mesenchymal Cell Activation , Excessive Hepatic Extracellular Matrix Deposition → Excessive ECM Deposition , Cirrhotic Architectural Distortion and Functional Failure → Architectural Distortion and Organ Dysfunction

Alpha-1 Antitrypsin Deficiency via Hepatic Stellate Cell Activation → Mesenchymal Cell Activation

Asbestosis via Biopersistent asbestos fiber deposition → Tissue Injury , Chronic sterile alveolitis → Inflammatory Recruitment and Amplification , Myofibroblast differentiation → Mesenchymal Cell Activation , Excessive extracellular matrix deposition → Excessive ECM Deposition , Interstitial fibrosis and architectural distortion → Architectural Distortion and Organ Dysfunction

Asherman_Syndrome via Endometrial Basal Layer Injury → Tissue Injury , Post-Injury Inflammatory Response → Inflammatory Recruitment and Amplification , Myofibroblast Generation and Mesenchymal Activation → Mesenchymal Cell Activation , Non-Regenerative Fibrotic Repair and Excessive ECM Deposition → Excessive ECM Deposition , Intrauterine Adhesion Formation and Cavity Obliteration → Architectural Distortion and Organ Dysfunction

Biliary Atresia via Portal Mesenchymal Cell Activation → Mesenchymal Cell Activation , Fibro-obliteration of the Biliary Tree → Excessive ECM Deposition

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

CAPN5-Related Vitreoretinopathy via Fibrotic Proliferative Vitreoretinopathy and Progressive Blindness → Architectural Distortion and Organ Dysfunction

Caroli disease via Progressive Peribiliary Fibrosis → Excessive ECM Deposition

Chagas disease via Myocardial fibrosis and arrhythmogenic substrate → Excessive ECM Deposition

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

Endomyocardial Fibrosis via Chronic antigenic or toxic stimulus in a susceptible host → Tissue Injury , Sustained eosinophilia and Th2-skewed immune activation → Inflammatory Recruitment and Amplification , Fibroblast activation and excessive collagen deposition → Mesenchymal Cell Activation , Dense endocardial fibrous scar → Excessive ECM Deposition , Apical and inflow-tract cavity obliteration → Architectural Distortion and Organ Dysfunction

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

Familial Vesicoureteral Reflux via Ascending Infection and Acute Pyelonephritis → Tissue Injury , Renal Inflammatory Cell Recruitment → Inflammatory Recruitment and Amplification , Interstitial Myofibroblast Activation → Mesenchymal Cell Activation , Renal Cortical Scarring → Excessive ECM Deposition , Reflux Nephropathy and Progressive Nephron Loss → Architectural Distortion and Organ Dysfunction

Formaldehyde Poisoning via Fibrotic stricture formation → Architectural Distortion and Organ Dysfunction

Glycogen Storage Disease Type VI via Hepatic Stellate Cell Activation and Fibrogenesis → 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

Hypertrophic Cardiomyopathy 30, Atrial via Cardiac Fibroblast Activation → Mesenchymal Cell Activation , Left Atrial Fibrosis → Excessive ECM Deposition

Idiopathic Interstitial Pneumonia via Injury to the alveolar-interstitial compartment of unknown cause → Tissue Injury , Myofibroblast activation in the fibrosing entities → Mesenchymal Cell Activation , Progressive pulmonary fibrosis → Architectural Distortion and Organ Dysfunction

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

Mitral Valve Prolapse via Regional Left Ventricular Fibrosis → Excessive ECM Deposition

Paraquat Poisoning via TGF-beta-Driven Mesenchymal Transition of Alveolar Epithelium → Mesenchymal Cell Activation , Progressive Pulmonary Fibrosis → Excessive ECM Deposition

Pericarditis via Pericardial injury from a heterogeneous trigger → Tissue Injury , Fibrotic organization of the pericardium → Excessive ECM Deposition

Progressive Familial Intrahepatic Cholestasis via Hepatic Stellate Cell Activation and Biliary Fibrosis → Mesenchymal Cell Activation

Proliferative Vitreoretinopathy via RPE Epithelial-Mesenchymal Transition → Mesenchymal Cell Activation

Pulmonary Alveolar Microlithiasis via Interstitial Fibrosis and Restrictive Physiology → Architectural Distortion and Organ Dysfunction

Raine Syndrome via Gingival Fibroblast Activation via TGF-beta and YAP/TAZ → Mesenchymal Cell Activation , Excessive Gingival ECM Deposition and Calcification → Excessive ECM Deposition

Rheumatic Heart Disease via Chronic valve fibrosis, commissural fusion, and calcification → Excessive ECM Deposition

Sarcoidosis via Fibrotic Tissue Remodeling → Mesenchymal Cell Activation

Silicosis via Fibroblast-to-Myofibroblast Activation → Mesenchymal Cell Activation , Excess Collagen Deposition and Silicotic Nodule Formation → Excessive ECM Deposition

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

Asbestosis as Biopersistent asbestos fiber deposition

Asherman_Syndrome as Endometrial Basal Layer Injury

Dupuytren Contracture as Fascial Microinjury and Aberrant Wound Healing

Endomyocardial Fibrosis as Chronic antigenic or toxic stimulus in a susceptible host

Familial Vesicoureteral Reflux as Ascending Infection and Acute Pyelonephritis

Idiopathic Interstitial Pneumonia as Injury to the alveolar-interstitial compartment of unknown cause

Idiopathic Pulmonary Fibrosis as Repetitive alveolar epithelial injury and aberrant repair

Pericarditis as Pericardial injury from a heterogeneous trigger

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

Asbestosis as Chronic sterile alveolitis

Asherman_Syndrome as Post-Injury Inflammatory Response

Dupuytren Contracture as Profibrotic Signaling and Inflammatory Amplification

Endomyocardial Fibrosis as Sustained eosinophilia and Th2-skewed immune activation

Familial Vesicoureteral Reflux as Renal Inflammatory Cell Recruitment

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

Adenomyosis as Lesional Fibrosis and Myofibroblast Transdifferentiation

Alcohol-Associated Liver Disease as Hepatic Stellate Cell Activation

Alpha-1 Antitrypsin Deficiency as Hepatic Stellate Cell Activation

Asbestosis as Myofibroblast differentiation

Asherman_Syndrome as Myofibroblast Generation and Mesenchymal Activation

Biliary Atresia as Portal Mesenchymal Cell Activation

Budd-Chiari Syndrome as Congestive Hepatic Fibrosis

Dupuytren Contracture as Myofibroblast Activation and Contraction

Endomyocardial Fibrosis as Fibroblast activation and excessive collagen deposition

Eosinophilic Fasciitis as TGF-beta-Driven Fascial Fibroblast Activation

Familial Vesicoureteral Reflux as Interstitial Myofibroblast Activation

Glycogen Storage Disease Type VI as Hepatic Stellate Cell Activation and Fibrogenesis

Hepatic Fibrinogen Storage Disease as Hepatic Stellate Cell Activation

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

Hypertrophic Cardiomyopathy 30, Atrial as Cardiac Fibroblast Activation

Idiopathic Interstitial Pneumonia as Myofibroblast activation in the fibrosing entities

Idiopathic Pulmonary Fibrosis as Fibroblast activation and myofibroblast differentiation

IgG4-Related Disease as Storiform Fibrosis

Liver Cirrhosis as Hepatic Stellate Cell Activation

Paraquat Poisoning as TGF-beta-Driven Mesenchymal Transition of Alveolar Epithelium

Progressive Familial Intrahepatic Cholestasis as Hepatic Stellate Cell Activation and Biliary Fibrosis

Proliferative Vitreoretinopathy as RPE Epithelial-Mesenchymal Transition

Raine Syndrome as Gingival Fibroblast Activation via TGF-beta and YAP/TAZ

Sarcoidosis as Fibrotic Tissue Remodeling

Silicosis as Fibroblast-to-Myofibroblast Activation

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

Alcohol-Associated Liver Disease as Excessive Hepatic Extracellular Matrix Deposition

Asbestosis as Excessive extracellular matrix deposition

Asherman_Syndrome as Non-Regenerative Fibrotic Repair and Excessive ECM Deposition

Biliary Atresia as Fibro-obliteration of the Biliary Tree

Caroli disease as Progressive Peribiliary Fibrosis

Chagas disease as Myocardial fibrosis and arrhythmogenic substrate

Dupuytren Contracture as Excessive Collagen Deposition and Cord Formation

Endomyocardial Fibrosis as Dense endocardial fibrous scar

Familial Vesicoureteral Reflux as Renal Cortical Scarring

Hepatic Fibrinogen Storage Disease as Excessive Hepatic ECM Deposition

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

Hypertrophic Cardiomyopathy 30, Atrial as Left Atrial Fibrosis

Idiopathic Pulmonary Fibrosis as Excessive extracellular matrix deposition

Mitral Valve Prolapse as Regional Left Ventricular Fibrosis

Paraquat Poisoning as Progressive Pulmonary Fibrosis

Pericarditis as Fibrotic organization of the pericardium

Raine Syndrome as Excessive Gingival ECM Deposition and Calcification

Rheumatic Heart Disease as Chronic valve fibrosis, commissural fusion, and calcification

Silicosis as Excess Collagen Deposition and Silicotic Nodule Formation

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

Alcohol-Associated Liver Disease as Cirrhotic Architectural Distortion and Functional Failure

Asbestosis as Interstitial fibrosis and architectural distortion

Asherman_Syndrome as Intrauterine Adhesion Formation and Cavity Obliteration

CAPN5-Related Vitreoretinopathy as Fibrotic Proliferative Vitreoretinopathy and Progressive Blindness

Dupuytren Contracture as Digital Flexion Contracture and Hand Dysfunction

Endomyocardial Fibrosis as Apical and inflow-tract cavity obliteration

Familial Vesicoureteral Reflux as Reflux Nephropathy and Progressive Nephron Loss

Formaldehyde Poisoning as Fibrotic stricture formation

Idiopathic Interstitial Pneumonia as Progressive pulmonary fibrosis

Idiopathic Pulmonary Fibrosis as Architectural distortion and gas-exchange failure

Pulmonary Alveolar Microlithiasis as Interstitial Fibrosis and Restrictive Physiology

Volumetric Muscle Loss as Fibrotic Scar Replacement and Persistent Functional Deficit