Matrix biology of idiopathic pulmonary fibrosis: a workshop report of the national heart, lung, and blood institute

Abstract

A hallmark of idiopathic pulmonary fibrosis (IPF) is excessive and disordered deposition of extracellular matrix. Although the lung extracellular matrix normally plays an essential role in development and maintenance of lung tissue through reciprocal interactions with resident cells, the disordered matrix in the diseased lung is increasingly recognized as an active and important contributor to IPF pathogenesis. This working group summary from a recently conducted National Heart, Lung, and Blood Institute strategic planning workshop for IPF research highlights recent advances, challenges, and opportunities in the study of matrix biology in IPF. Particular attention is given to the composition and mechanical properties of the matrix in normal and diseased lungs, and the biochemical and biomechanical influences exerted by pathological matrix. Recently developed model systems are also summarized as key tools for advancing our understanding of matrix biology in IPF. Emerging approaches to therapeutically target the matrix in preclinical and clinical settings are discussed, as are important concepts, such as alterations of the matrix with aging and the potential for the resolution of fibrosis. Specific recommendations for future studies in matrix biology of IPF are also proposed.

Figure 1

Biochemical and biomechanical interactions between fibroblasts and the ECM. Biochemical and biomechanical stimuli derived from the fibrotic ECM initiate intracellular signals through multiple pathways. Integrin, microfilament, and transcription factor–mediated signals are highlighted. These signals promote the fibrogenic phenotype of fibroblasts. Reciprocally, cellular signals can feedback to the ECM and regulate the composition and mechanical properties of the ECM. These bidirectional interactions between fibroblasts and the ECM provide positive feedback loops that sustain/perpetuate progression of lung fibrosis. TAZ, transcriptional coactivator with PDZ-binding motif; YAP, yes-associated protein.

Figure 2

Potential matrix-directed therapeutic strategies for lung fibrosis.