Disorders of lung matrix remodeling

Abstract

A set of lung diseases share the tendency for the development of progressive fibrosis ultimately leading to respiratory failure. This review examines the common pathogenetic features of these disorders in light of recent observations in both humans and animal models of disease, which reveal important pathways of lung matrix remodeling.

Figure 1

Photomicrographs of active matrix remodeling in: (a) UIP, (b) BO, and (c) COP. Filled arrows point to areas of active matrix remodeling in each disorder. Open arrows point to airway or alveolar epithelial cells overlying the remodeling matrix. Images were kindly provided by Kirk Jones, Department of Pathology, University of California, San Francisco, San Francisco, California, USA. Magnifications: (a, b) ×400; (c) ×100.

Figure 2

Determinants of lung response to breakdown in epithelial barrier function. (a) Coordinated processes of tissue factor/factor VII complexes initiating thrombin formation and plasminogen activation by urokinase (uPA). Plasmin facilitates initial exudate turnover. Ingrowth of fibroblasts and organization of exudates into a collagenous matrix occurs quickly. (b) Maintenance of epithelial integrity, resorption of ECMs by AMs, and fibroblast apoptosis favor resolution. (c) Epithelial cell apoptosis, activation of receptors of the profibrotic cytokines thrombin, leukotrienes, and TGF-β₁, and persistence of the ECM secondary to excess protease inhibitors (PAI-1 and tissue inhibitor of metalloprotease) with accumulation of fibroblast growth factors (IGF, PDGF, CTGF) favors fibrosis.

Figure 3

Pre- and postreceptor regulation of TGF-β₁ signaling. Latent TGF-β₁ can be activated by proteases (such asMMPs, plasmin) and by binding to TSP-1 or the integrin α_vβ₆, expressed on epithelial cells. Signaling through the TGF-β₁ receptor leads to phosphorylation of SMADs 2 and 3 and their translocation to the nucleus to mediate transcription of target genes. IFN-γ and IL-7 induce counter-regulatory SMAD 7. Cellular responses to TGF-β₁ signaling are modulated by concurrent signaling through growth factor (GF) and adhesion receptors (β1 integrins). Integrated inputs from the pathways shown in the figure link deposition and turnover of ECM elements and GFs to expansion of mesenchymal elements such as fibroblasts and smooth muscle cells and the matrix proteins they secrete. Chemokines acting through G protein–coupled receptors also modulate TFβ1 responses (not shown).