Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

Abstract

Pulmonary fibrosis is a vexing clinical problem with no proven therapeutic options. In the normal lung there is continuous collagen synthesis and collagen degradation, and these two processes are precisely balanced to maintain normal tissue architecture. With lung injury there is an increase in the rate of both collagen production and collagen degradation. The increase in collagen degradation is critical in preventing the formation of permanent scar tissue each time the lung is exposed to injury. In pulmonary fibrosis, collagen degradation does not keep pace with collagen production, resulting in extracellular accumulation of fibrillar collagen. Collagen degradation occurs through both extracellular and intracellular pathways. The extracellular pathway involves cleavage of collagen fibrils by proteolytic enzyme including the metalloproteinases. The less-well-described intracellular pathway involves binding and uptake of collagen fragments by fibroblasts and macrophages for lysosomal degradation. The relationship between these two pathways and their relevance to the development of fibrosis is complex. Fibrosis in the lung, liver, and skin has been associated with an impaired degradative environment. Much of the current scientific effort in fibrosis is focused on understanding the pathways that regulate increased collagen production. However, recent reports suggest an important role for collagen turnover and degradation in regulating the severity of tissue fibrosis. The objective of this review is to evaluate the roles of the extracellular and intracellular collagen degradation pathways in the development of fibrosis and to examine whether pulmonary fibrosis can be viewed as a disease of impaired matrix degradation rather than a disease of increased matrix production.

Keywords: UIP; collagen degradation; extracellular matrix; matrix metalloproteinases; pulmonary fibrosis.

Fig. 1.

Many etiologies can induce a fibrotic response in the lung, but fibrosis only persists in certain types of disease. ECM, extracellular matrix; UIP, usual interstitial pneumonitis; ARDS, acute respiratory distress syndrome.

Fig. 2.

Collagen synthesis begins with the translation of collagen pro-α chains in the rough endoplasmic reticulum. After these chains form a triple helix, the molecule is secreted from the cell, where it undergoes further processing and aggregation into fibrils and fibers.

Fig. 3.

Collagen monomers are incorporated into fibrils, which aggregate to form fibers. Degradation of collagen fibers involves cleavage of fibrils by collagenolytic enzymes and uptake of collagen fragments by macrophages and fibroblasts or further cleavage by gelatinases. MMP, matrix metalloproteinase.

Fig. 4.

Collagen internalization is mediated by macropinocytic, phagocytic, and endocytic pathways. Multiple cell-surface receptors have been shown to bind collagen, but the majority of those act to tether the cell to the ECM or relay signals from the ECM to the intracellular compartment. The receptors shown above have been shown to specifically mediate internalization of bound collagen fragments.