L8: Molecular and Cellular Mechanism of Fibrosis

What is tissue fibrosis?

A wound-healing response that fails to resolve, characterized by ECM accumulation and qualitative/quantitative changes in ECM components due to imbalance between synthesis and degradation.

What role do cytokines and growth factors play in tissue fibrosis?

They contribute to the activation of fibroblasts, inflammation, and the synthesis of extracellular matrix components.

How do pericytes contribute to fibrosis?

Pericytes migrate from blood vessels, differentiate into myofibroblasts, and secrete ECM components upon stimulus, such as injury of epithelial or endothelial tissue.

What is epithelial-to-mesenchymal transition (EMT)?

(1) Dissociation of tight junctions and loss of microvilli; (2) Loss of apical-basal polarity; (3) Cytokeratin reorganization and mesenchymal marker expression.

Name three key inducers of EMT during fibrosis.

TGF-β1, Notch signaling, NF-κB signaling, and HA fragments.

How does fibrosis impact tissue function?

Fibrosis can lead to tissue stiffening, impaired function, and ultimately organ failure.

What is the function of the extracellular matrix (ECM)?

Provides structural support, binds to cell receptors, aids in tissue formation, and regulates cellular behavior.

What are the main components of the extracellular matrix?

Collagen, laminin, fibronectin, and proteoglycan, which vary in proportions across different organs.

What is the key role of TGF-β1 in tissue fibrosis?

TGF-β1 promotes myofibroblast differentiation and ECM synthesis through Smad-dependent and Smad-independent pathways.

What is the role of macrophages in tissue fibrosis?

They release growth factors and TGF-β, promote inflammation and chemotaxis of inflammatory cells, and remodel the ECM.

What triggers the activation of resident fibroblasts in tissue fibrosis?

Stimuli such as stress, growth factors, hypoxia, reactive oxygen species, and cytokines.

What is the role of fibronectin in the ECM?

Facilitates cell adhesion, migration, growth, and differentiation while serving as a scaffold for other matrix proteins.

What is the significance of decorin in ECM regulation?

It interacts with membrane receptors to influence cell behavior and forms complexes with TGF-β1 to inhibit its activity.

How does ERK signaling contribute to fibrosis?

ERK (a MAPK subfamily member) regulates cytokine production (e.g., IL-6) in macrophages.

How does collagen I contribute to tissue stiffening?

Collagen I accumulation increases TGF-β1, reduces degradation, and forms cross-links resistant to MMPs.

What is the role of decorin in the ECM?

Decorin binds TGF-β1 to inhibit its activity and regulates collagen fiber assembly.

How do cancer-associated fibroblasts differ from NAF?

They undergo irreversible epigenetic changes, produce lactate for self-activation, and secrete distinct ECM proteins (e.g., tenascin, periostin).

What three pathophysiologic events drive fibrosis?

(1) Chemotaxis of inflammatory cells; (2) Increased microvascular permeability/adhesion; (3) Activation of resident/infiltrating cells.

How does soluble fibronectin influence fibrosis?

Induces MCP-1 secretion in tubular cells (promoting inflammation) and acts as a chemoattractant for myofibroblasts.

What mesenchymal markers are acquired during EMT?

Vimentin, fibronectin, collagen I, α-smooth muscle actin, fibroblast-specific protein-1, and SNAIL.

What distinguishes fibrosis-associated fibroblasts from normal fibroblasts?

Irreversible activation, high proliferation, lactate production, and secretion of pro-fibrotic factors (IL-8, CXCL7).