Interfering with extracellular matrix degradation to blunt inflammation

Abstract

Chemoattractant properties of matrix proteins, like collagen and elastin, for neutrophils and monocytes in vitro have long been recognized. This activity often resides in fragments of these proteins. These peptides may play a role in diseases of the lung matrix, such as chronic obstructive pulmonary disease. Recent advances include the elucidation of the structure of chemotactic collagen fragments and the demonstration that their activity may reside in a structural relatedness to CXC chemokines. Collagen and elastin fragments have been demonstrated to have a role in in vivo lung pathophysiology and have been quantified in patients with chronic lung diseases where they may activate autoimmune pathways. Elucidation of these pathways may provide novel biomarkers and therapeutic targets for chronic lung diseases.

Figure 1

Airway epithelium is damaged, often from infection, leading to the release of monocyte chemoattractants, such as MCP-1, into the interstitium. Increased concentrations of MCP 1 in the interstitium induce chemotaxis of monocytes from the vascular space via CCR2 binding. Activated monocytes release MMP-12 and other MMPs and activated neutophils release HNE which cleave elastin into fragments containing the motifs GXXPG or XGXPG. These fragments act on elastin receptors on monocytes to induce further monocyte recruitment and perpetuate damage to the lung.

Figure 2

Airway epithelium is damaged, often from infection, leading to the release of IL-8 into the interstitium. Increased concentrations of IL-8 in the interstitium induce chemotaxis of neutrophils from the vascular space via a CXCR 1/2 mechanism. Activated neutrophils release MMP-9 which cleaves collagen into fragments containing PGP. PGP acts on CXCR to induce further neutrophil recruitment and perpetuate damage to the lung.