New Mechanisms of Pulmonary Fibrosis

doi:10.1378/chest.09-0510

Chest

Volume 136, Issue 5, November 2009, Pages 1364-1370

https://doi.org/10.1378/chest.09-0510 Get rights and content

The understanding of the pathogenesis of pulmonary fibrosis continues to evolve. The initial hypothetical model suggested chronic inflammation as the cause of pulmonary fibrosis, whereas a subsequent hypothesis posited epithelial injury and impaired wound repair as the etiology of fibrosis without preceding inflammation. Over the past decade, several concepts have led to refinement of these hypotheses. These include the following: (1) the importance of the integrity of the alveolar-capillary barrier basement membrane (BM) to conserving the architecture of the injured lung; (2) conversely, that the failure of reepithelialization and reendothelialization of this BM results in pathologic fibrosis; (3) transforming growth factor-β is necessary but not sufficient to the pathologic fibrosis of the lungs; (4) the role of persistent antigens in the pathogenesis of usual interstitial pneumonia; and (5) the contribution of epithelial-to-mesenchymal transformation and bone marrow-derived progenitor cells in the pathogenesis of lung fibrosis. In this review, we will discuss these evolving conceptual mechanisms for the pathogenesis of pulmonary fibrosis relevant to idiopathic pulmonary fibrosis.

Section snippets

Loss of Alveolar-Capillary Barrier BM Integrity as the Point of No Return

The alveolar-capillary barrier represents the gas exchange surface of the lungs and is, by far, the largest surface area within the lungs that separates the interior of the body from the environment. Ultrastructurally, this barrier is composed of the type I alveolar epithelial cell, the capillary endothelial cell, and their respective BMs. Over about one-half of the barrier, the two BMs are fused, and in the remainder they are separated by a thin sheet of interstitium. Since both the epithelial

Failure of Reepithelialization and Reendothelialization Due to the Loss of Alveolar-Capillary Barrier BM Leads to Destroyed Lung Architecture and Fibrosis

An ultrastructural analysis of tissue from the lungs of patients with IPF demonstrated the following: (1) both type I pneumocyte and endothelial cell injury with loss of integrity of the alveolar-capillary barrier BM8, 9, 10, 11, 12, 13, 14; (2) intraalveolar deposition of ECM with accumulation of fibroblasts and myofibroblasts; and (3) obliteration and fibrosis of the alveoli with fusion of adjacent alveolar-capillary barrier BM residual structures, leading to the development of fibroblastic

Cytokine Mediators of Lung Fibrosis and Loss of Tissue Architecture

TGF-β is a pleiotropic cytokine that has been found to be highly associated in promoting fibrosis. TGF-β itself has been found to promote fibrosis in the lung. Adenoviral transgenic delivery and the overexpression of active TGF-β promotes marked fibrosis in rodent models.¹⁷ However, in another study,¹⁸ conditional transgenic mice were generated that express active TGF-β in airway cells. TGF-β overexpression led to peribronchial fibrosis with extension to the adjacent lung parenchyma.¹⁸ In

The Pathogenesis of Usual Interstitial Pneumonitis Is a Process Related to a Persistent “Antigen” That Promotes Chronic Inflammation, Destruction of Lung Architecture, and Progressive Fibrosis

In addition to IPF (which is defined as idiopathic UIP), the histologic pattern of UIP is also found in asbestosis (in the context of a persistent inorganic irritant), hypersensitivity pneumonitis (recurrent exposure to exogenous antigens), and collagen vascular diseases such as rheumatoid arthritis or scleroderma (recurrent exposure to self antigens).¹⁴ Thus, in each of the illnesses when UIP is attributable to a known cause, it is the result of a persistent or repetitive insult that leads to

EMT and Fibrocytes Are Critical Cellular Players in the Regulation of Fibrosis

Since lung fibroblasts and myofibroblasts play an important role in ECM deposition in pulmonary fibrosis, the origin of the expanded populations of these cells in the lungs is of substantial interest. There is one classic theory and two contemporary theories for the origin of fibroblasts/myofibroblasts.13, 42 The classic concept is that tissue injury induces the activation of a resident fibroblast to proliferate and express constituents of the ECM. The contemporary theory is that tissue injury

Conclusions

In summary, the loss of the alveolar-capillary barrier BM integrity is critical in determining the point of no return, which leads to the promotion of fibrosis. The loss of epithelial cells, endothelial cells, and alveolar-capillary barrier BM integrity in patients with UIP associated with IPF leads to destroyed lung architecture and perpetual fibrosis. The anatomical target that leads to the hallmark features of UIP may be the anatomical respiratory lobule. TGF-β is necessary but not entirely

Acknowledgments

Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest with any companies/organizations whose products or services discussed in this article.

References (0)

Cited by (0)

Funding/Support: National Institutes of Health grants CA87879 and HL66027.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

View full text