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Originally published online as doi:10.2353/ajpath.2009.081170 on June 4, 2009

Published online before print June 4, 2009
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(American Journal of Pathology. 2009;175:3-16.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.081170

Review

Emerging Concepts in the Pathogenesis of Lung Fibrosis

William D. Hardie*, Stephan W. Glasser* and James S. Hagood{dagger}

From the Department of Pediatrics* (Pulmonary Medicine and Pulmonary Biology), Cincinnati Children’s Medical Center, Cincinnati, Ohio; and the Department of Pediatrics{dagger} (Pulmonary Division and Translational Research in Normal and Disordered Development Program), University of Alabama-Birmingham, Birmingham, Alabama

Fibrogenesis is an often-deadly process with increasing world-wide incidence and limited therapeutic options. Pulmonary fibrogenesis involves remodeling of the distal airspace and parenchyma of the lung, and is characterized by excessive extracellular matrix deposition and accumulation of apoptosis-resistant myofibroblasts. Recent studies have added significantly to our understanding of the complex mechanisms involved in lung fibrogenesis. Emerging concepts in this field include the critical role of the epithelium, particularly type II pneumocytes, in the initiation and perpetuation of fibrosis in response to either endogenous or exogenous stress; a growing awareness of alternative activation of macrophages in tissue remodeling; growing appreciation of the alternative origins and phenotypic plasticity of fibroblasts; the roles of epigenetic reprogramming and context-dependent signaling in profibrotic phenotype alterations; and recognition of the importance of cross talk and convergence of intracellular signaling pathways. In vitro, in vivo, and in silico approaches support a paradigm of "disordered re-development" of the lung. Designing effective antifibrotic interventions will require accurate understanding of the complex interactions among the genetic, environmental, epigenetic, biochemical, cellular, and contextual abnormalities that promote pulmonary fibrogenesis.






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