Permanent alveolar collapse is the predominant mechanism in idiopathic pulmonary fibrosis

Abstract

Alveolar epithelial cell loss and impaired epithelial cell regeneration are currently accepted as central initiating events in idiopathic pulmonary fibrosis (IPF), but subsequent downstream effects remain uncertain. The most accepted downstream effect is aberrant and dysregulated mesenchymal cell proliferation and excess extracellular matrix (ECM) accumulation. However, biochemical and imaging studies have perhaps somewhat surprisingly indicated little increase in total lung collagen and lung tissue, and have rather shown a substantial decrease in lung aeration and lung air volume. Loss of tissue aeration is a consequence of alveolar collapse, which occurs in IPF as a result of apposition and septal incorporation of denuded basal lamina. Permanent alveolar collapse is well-documented following epithelial injury, has the ability to mimic interstitial fibrosis radiologically and histologically, and is a better supported explanation than dysregulated fibroblast proliferation and excess ECM accumulation for the constellation of findings in patients with IPF.

Keywords:

• alveolar collapse
• collagen
• collapse induration
• epithelial cell injury
• extracellular matrix
• idiopathic pulmonary fibrosis

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Idiopathic pulmonary fibrosis (IPF) is a severely debilitating lung disease with limited efficacious therapies, and with an overall median survival of 3 years.

• Alveolar epithelial cell loss and impaired epithelial cell regeneration are likely central initiating events, but subsequent downstream effects remain uncertain.

• Excess extracellular matrix (ECM) accumulation, resulting from dysregulated mesenchymal cell proliferation, is commonly accepted as the major abnormality in IPF, and has been targeted by therapeutic interventions.

• Perhaps somewhat surprisingly, biochemical and imaging studies have shown either no increase or only a mild increase in total lung collagen and total lung tissue in IPF, which does not support an excess accumulation of ECM as the major abnormality.

• IPF studies have, on the other hand, shown a substantial decrease in lung aeration and lung air volume.

• Alveolar collapse is associated with loss of lung tissue aeration, is well-documented to occur following epithelial injury and has the ability to mimic interstitial fibrosis radiologically and histologically.

• Histologic observations have shown that epithelial cell injury leads to denuded basal lamina, apposition and septal incorporation of basal lamina and permanent alveolar collapse.

• Epithelial cell injury followed by permanent alveolar collapse and permanent loss of tissue aeration is a much better supported explanation than dysregulated mesenchymal cell proliferation and excess extracellular matrix accumulation for the constellation of findings in patients with IPF.