We describe the tripeptide neutrophil chemoattractant N-acetyl Pro-Gly-Pro (PGP), derived from the breakdown of extracellular matrix (ECM), which shares sequence and structural homology with an important domain on alpha chemokines. PGP caused chemotaxis and production of superoxide through CXC receptors, and administration of peptide caused recruitment of neutrophils (PMNs) into lungs of control, but not CXCR2-deficient mice. PGP was generated in mouse lung after exposure to lipopolysaccharide, and in vivo and in vitro blockade of PGP with monoclonal antibody suppressed PMN responses as much as chemokine-specific monoclonal antibody. Extended PGP treatment caused alveolar enlargement and right ventricular hypertrophy in mice. PGP was detectable in substantial concentrations in a majority of bronchoalveolar lavage samples from individuals with chronic obstructive pulmonary disease, but not control individuals. Thus, PGP's activity links degradation of ECM with neutrophil recruitment in airway inflammation, and PGP may be a biomarker and therapeutic target for neutrophilic inflammatory diseases.

The observation that only 50% of patients with adult asthma manifest atopy indicates that other inflammatory mechanisms are likely involved in producing the characteristic features of this disorder; namely reversible airway obstruction, hyperresponsiveness, and pulmonary inflammation. Our recent discovery that antigen-specific Ig free light chains (LCs) mediate hypersensitivitylike responses suggests that these molecules may be of import in the pathophysiology of asthma. Using a murine experimental model of nonatopic asthma, we now have shown that an LC antagonist, the 9-mer peptide F991, can abrogate the development of airway obstruction, hyperresponsiveness, and pulmonary inflammation. Further, passive immunization with antigen-specific LCs and subsequent airway challenge can elicit a mast cell-dependent reaction leading to acute bronchoconstriction. These findings, and the demonstration that the concentration of free LCs in the sera of patients with adult asthma were significantly increased (as compared with age-matched nonasthmatic individuals), provide previously undescribed insight into the pathogenesis of asthma. In addition, the ability to inhibit pharmacologically LC-induced mast cell activation provides a therapeutic means to prevent or ameliorate the adverse bronchopulmonary manifestations of this incapacitating disorder.mast cells ͉ lung A sthma is a relatively common disorder manifested by airway inflammation that leads to bronchoconstriction and respiratory symptoms. Approximately 50% of adults with this disorder have atopic manifestations that involve IgE-mediated tissue sensitization with a T helper cell 2 response and eosinophilia (1, 2). However, that an equal percentage of patients with asthma are not atopic, as evidenced by negative skin-prick test as well as normal serum IgE levels and eosinophil counts (1, 2), indicates that other causative factors may be involved in the etiology of this disease. Furthermore, standardized comparisons across populations or time show only a weak and inconsistent association between the prevalence of adult asthma and the prevalence of atopy (1).Mast cells have been implicated as essential elements in the asthmatic process (3-5). Indeed, mast cell numbers are increased in the lungs of individuals with atopic as well as nonatopic variants of adult asthma, and the extent of degranulation of these cells is directly related to disease severity (6, 7). Although antigen-specific mast cell activation results from crosslinking of the high-affinity IgE receptor, FcRI, this effect can also occur in the absence of IgE antibodies (8-12); furthermore, anti-IgE antibody therapy has been of limited benefit in asthma (13-18).Our recent discovery that Ig free light chains (LCs) mediate antigen-specific mast cell-dependent hypersensitivity-like responses suggests that these molecules could be involved in the pathophysiology of adult asthma (19). We showed that mice, passively sensitized with antigen-specific LCs, when challenged by cutaneous exposure to the antigen, developed an...

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In patients with chronic obstructive pulmonary disease (COPD), an inflammatory process is ongoing in the lungs, with concomitant damage of the alveolar structures and loss of airway function. In this inflammatory process, extracellular matrix degradation is observed. During this lung matrix degradation, small peptide fragments consisting of proline and glycine repeats generated from collagen fibers are liberated from the matrix by matrix metalloproteinases. Chemotactic activities of these collagen-derived peptides such as N-acetyl-proline-glycine-proline (PGP) via CXCR1 and CXCR2 have been reported. We show here that PGP induces neutrophil migration in vivo, which is dose dependent. Moreover, PGP is involved in the development of emphysema-like changes in the airways. The complementary peptide, L-arginine-threonine-arginine (RTR), has been shown to bind to PGP sequences and inhibit neutrophil infiltration. We show that RTR impedes both PGP- and interleukin-8-induced chemotaxis in vitro. In vivo, RTR prevents both migration and activation of neutrophils induced by PGP. Furthermore, RTR completely inhibits PGP-induced lung emphysema, assessed by changes in alveolar enlargement and right ventricular hypertrophy. In conclusion, these data indicate that collagen breakdown products, especially PGP, are important in the pathogenesis of COPD and that PGP antagonism via RTR ameliorates lung emphysema.