Chair’s Summary: Lung Injury and Repair: Role of Extracellular Matrix

It has long been recognized that net deposition or loss of matrix proteins such as collagen and elastin are central features of the pathogenesis of respiratory diseases. Indeed, in the fibrotic lung disorders, considerable research has been directed toward understanding the molecular mechanisms leading to fibroblast proliferation and the excessive and deranged deposition of collagen. It has also been recognized for many years that acute lung injury may, in some patients, involve very rapid activation of matrix deposition, and in acute respiratory distress syndrome this can manifest as catastrophic scarring within a few weeks of injury. More recently, matrix has become the focus of research in the setting of other respiratory diseases. In asthma there is a so-called subepithelial fibrosis that occurs even in young subjects with asthma and the intransigence of this scar tissue to current therapy may explain the inability to treat up to 20% of patients with asthma who do not respond well to current therapies. In chronic obstructive pulmonary disease, the pioneering work of Hogg and his colleagues in Vancouver has led to the view that small airways fibrosis is central to disease pathogenesis of emphysema and may precede the destructive phase with airspace enlargement. In pulmonary hypertension, there is also much interest in the adventitial changes with excessive deposition of matrix. Indeed, the endothelin receptor antagonists that have found a place in the treatment of this disease are believed to target fibroblasts as well as exert their well-known vasoactive effects. The advance in our understanding of matrix biology has been extraordinary over the last 30 to 40 years. We now recognize that extracellular matrix is a complex structure, with a diverse group of molecules interacting with each other and their environment. Some are playing the classical structural role, but others are performing key roles in signaling into andbetween the 40 different cell types that constitute the lung. Indeed, the roles of these networks and particularly the integrin family of cell surface receptors in transducing pathways leading to release and activation of growth factors, such as transforming growth factor-b, was highlighted in this meeting. Another major development is in our understanding of the various mechanisms that can lead to increased numbers of myofibroblasts in the injured lung and the multitude of mechanism that can lead to their activation. In this meeting, various experts highlighted the roles of lipid mediators, proteases, and a host of novel cytokines and growth factors. The participants also debated the pharmacological challenges associated with a disease in which there seems to be a diversity of cascades leading to fibrosis. Recent datawere also presented exploring the role of epithelial– mesenchymal transition in pulmonary fibrosis. This remains controversial, as does the nature of the profibrotic phenotype of the cells this process produces. The mechanistic complexity has also been matched by the genetic complexity. Careful studies over the last 20 years have revealed many genes, and the recent more focused screens have highlighted genes and pathways that are of interest because they are not always associated with the classic pathways leading to fibrosis. This issue of the Proceedings of the American Thoracic Society gives us insight into the most recent developments and opportunities. It also provides a road map for the future by highlighting areas in which we urgently need more research. All of us in the field remain hopeful that the ongoing developments in basic science will be accompanied by the development of new pharmacological approaches to treat fibrotic lung disorders. These are urgently needed, and continued investment in this area makes us all optimistic that breakthroughs are not too far away.

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