Influences of innate immunity, autophagy, and fibroblast activation in the pathogenesis of lung fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease characterized by accumulation of extracellular matrix (ECM) and impaired gas exchange. The pathobiological mechanisms that account for disease progression are poorly understood but likely involve alterations in innate inflammatory cells, epithelial cells, and fibroblasts. Thus we seek to review the most recent literature highlighting the complex roles of neutrophils and macrophages as both promoters of fibrosis and defenders against infection. With respect to epithelial cells and fibroblasts, we review the data suggesting that defective autophagy promotes the fibrogenic potential of both cell types and discuss new evidence related to matrix metalloproteinases, growth factors, and cellular metabolism in the form of lactic acid generation that may have consequences for promoting fibrogenesis. We discuss potential cross talk between innate and structural cell types and also highlight literature that may help explain the limitations of current IPF therapies.

Keywords: epithelial cells; fibroblasts; fibrosis; innate immunity; lung.

Fig. 1.

Schematic depicting recent insights into pathogenesis of pulmonary fibrosis. Pulmonary fibrosis is influenced by the orchestration of epithelial, mesenchymal, and immune interactions. Recent data highlight the important roles of innate immune cells, especially monocytes and neutrophils, in regulating TGFβ activation, fibroblast phenotypes, and epithelial injury. Additionally, immune dysfunction may lead to infections that can exacerbate lung fibrosis. Autophagy plays an important role in epithelial cell response to stressors and autophagy is impaired by profibrotic factors such as IL-17 and TGFβ that can be delivered by innate immune cells. Metabolic changes resulting in release of lactic acid are now appreciated to activate TGFβ to drive myofibroblast activation. Additionally, MMPs and fibroblast growth factors influence fibroblast phenotypes in lung fibrosis as well. The concepts highlighted in the boxes are the subject of this review of recent literature.