Posted by: Dan | May 22, 2007

RP: Story of the Chemokine-Mimicking Collagen Fragment

For some reason, this post from 13 months ago has been consistently getting the most google-directed traffic as of late. It was originally posted on my first blog over 13 months ago, so it’s ripe for the reposting…


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Nature Medicine has an interesting article out in [March 2006]’s issue, detailing how a acetylated peptide fragment from the extracellular matrix protein collagen mimics key sequences of the neutrophil attractant Interleukin-8 (IL-8). The acetylated tripeptide, acPGP, induces neutrophil chemotaxis in vitro and emigration in vivo – important early steps in the inflammatory response.

Thus, Weathington et al. eludicate a mechanism by which damaged tissue recruits immune cells to possible sites of infection. Beyond simply expanding our understanding of how the most abundant mammalian protein might contribute to the inflammatory process, Weathington and colleagues suggest that acPGP might play a role in chronic obstructive pulmonary disease (COPD), which is primarily a systemic inflammatory disease of the lung that is induced by cigarette smoke. Characterized by the presence of emphysema and chronic bronchitis, COPD is predicted to become the third most common cause of death worldwide by 2020.

Specifically, Weathington et al. present preliminary evidence that acPGP is present in the lungs of some individuals with COPD, but it is unclear whether this represents a cause of COPD-related emphysema and pulmonary hypertension, or a concurrent effect of inflammation – not suggesting a greater pathogenic role than any other neutrophil chemoattractant. Further, the authors showed that generation of acPGP in an inflammatory response in mice and emphasema-like symptoms is only transiently correlated.

Weathington et al. note that the chemoattractant properties of PGP-containing properties and the induction of lipopolysaccharide (LPS)-induced inflammation have been documented since 1970, but this is the first evidence for action through the IL-8 receptors CXCR1 and CXCR2. While they mention and discuss several questions for future study, the interesting parts are the potential therapeutic routes for pathogenic inflammation.

Antagonizing chemokines and leukotrienes incompletely block neutrophil chemotaxis to human COPD samples. Detection of PGP in samples from individuals with COPD could explain residual chemotactic activity, and may account for long-term sequelae seen in chronic inflammation. Although the concentration of PGP in the BAL fluid is below its chemotactic threshold, it becomes more relevant when we account for the 1:100 dilution of airway lining fluid by the lavage process reported in earlier human studies, placing the in situ concentration of diffusible PGP around 0.1micromolar. Larger peptides containing the PGP sequence possess similar chemotactic activity, and could also contribute to overall chemotaxis, though such species have not been measured. Future longitudinal studies in humans for multiple PGP-related peptides, perhaps with breath-condensate samples, will probably best determine the contribution of this pathway to airway disease and use as a disease marker.

Clinical findings with IL-8–specific monoclonal antibodies40 in individuals with COPD implies that cell trafficking is a realistic therapeutic target for inflammatory diseases. The activity of PGP as a PMN chemoattractant may represent another target. This idea is consistent with the protease-antiprotease hypothesis of airway diseases, and is corroborated by assertions that breakdown of ECM may be an important therapeutic target in chronic airway diseases, and that tissue damage is self-sustaining. PGP signaling through CXCRs on neutrophils indicates that combining MMP blockade with chemokine receptor antagonism may dampen multiple modalities of neutrophil recruitment in acute and chronic inflammation, and could potentially prevent the extensive tissue damage and remodeling seen in advanced disease.

  • Weathington, N.M. et al. Nat. Med. 12, 317–323 (2006).
  • Peter M Henson & R William Vandivier Nat. Med. 12, 280 – 281 (2006).

Responses

  1. Many baby boomers think that the symptoms they have are due to old age when they are actually signs of more serious things like COPD.

    As a writer and assistant editor at Hello Boomers Magazine I come accross many subjects and issues important to baby boomers. The boomers have many questions and concerns and a website like yours is an important source of information related to their specific situation.


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