Lung inflammation leads to the production of chemokines and the recruitment of neutrophils. However, peptides derived from the proteolytic cleavage of collagen such as N-acetyl Pro-Gly-Pro (PGP) have also been shown to function as neutrophil chemoattractants. A new study in Nature Medicine examines the molecular basis of PGP's activity and its potential role in chronic obstructive pulmonary disease (COPD).

Blalock and colleagues show that intratracheal administration of purified PGP leads to a remarkable increase in the number of neutrophils in mouse lungs. In agreement with the in vivo data, transwell chemotaxis assays confirm that PGP acts as a neutrophil chemoattractant.

To determine how PGP recruits neutrophils into the airways, the authors carried out a sequence comparison between a collagen fragment possessing the PGP sequence and similar sequences contained in the well-established neutrophil attractants - the Glu-Leu-Arg motif-containing CXC (CXC) chemokines. Not only did they find a conserved PPGPH sequence, but comparison of the available structures also revealed a structural homology between PGP and the CXC chemokines.

The authors went on to investigate whether PGP and CXC chemokines signal through the same receptors by examining neutrophil chemotaxis upon exposure to PGP or the CXC chemokine IL-8, and antibodies that target the chemokine receptors CXCR1 and CXCR2. When the receptors were blocked, neither IL-8 nor PGP were able to stimulate migration. Furthermore, both IL-8 and PGP induced the production of superoxide, which results from CXCR1 ligation, and importantly, exposure to PGP did not lead to the accumulation of neutrophils in the airways of Cxcr2^-/- mice. Together, these results suggest that PGP activity is mediated by CXCR1 and CXCR2.

So, what is the physiological role of PGP? The authors found that exposure to lipopolysaccharide (LPS), which mimics lung infection and induces tissue breakdown, leads to the production of PGP. The collagen-derived peptides in bronchoalveolar fluids after LPS exposure were active neutrophil chemoattractants in vitro. Moreover, two symptoms of COPD — alveoli enlargement and right ventricular hypertrophy — were observed after chronic administration of PGP. Interestingly, high levels of PGP were also detected in 3 out of 5 COPD patients.

The findings of this study suggest that PGP is a potential contributor to COPD and that it could be a useful marker of the disease. This ability of PGP, and other peptides of similar sequence, to mimic IL-8 has important implications for the regulation of inflammation and the development of new therapeutic agents.

Author: Monica Hoyos-Flight