Objectives-Trauma predisposes to systemic sterile inflammation (SIRS) as well as infection, but the mechanisms linking injury to infection are poorly understood. Mitochondrial debris (MTD) contains formyl peptides (mtFPs). These bind formyl peptide receptor-1 (FPR1), trafficking neutrophils (PMN) to wounds, initiating SIRS and wound healing. Bacterial FPs (bFPs) however, also attract PMN via FPR1. Thus mtFPs might suppress PMN antimicrobial function. Also, FPR1 blockade used to mitigate SIRS might predispose to sepsis. We examined how mtFPs impact PMN functions contributing to antimicrobial responses, and how FPR1 antagonists affect those functions. Design-Prospective study of human and murine PMN and clinical cohort analysis.Setting-University research laboratory and Level 1 trauma center. Patients-Trauma patients, volunteer controls.Animal subjects-C57Bl/6, FPR1, and FPR2 knockout mice.Interventions-Human and murine PMN functions were activated with autologous MTD, mtFPs or bFPs followed by chemokines or leukotrienes. The experiments were repeated using FPR1 antagonist cyclosporin H (CsH), 'designer' human FPR1 antagonists (POL7178 and POL7200) or
BackgroundPotential involvement of the CCR10/CCL28 axis was recently reported in murine models of allergic asthma. If confirmed, blockade of the CCR10 receptor would represent an alternative to current asthma therapies. We evaluated the effect of a novel Protein Epitope Mimetic CCR10 antagonist, POL7085, in a murine model of allergic eosinophilic airway inflammation.MethodsMice were sensitized and challenged to ovalbumin. POL7085, a CCR10 antagonist (7.5 and 15 mg/kg), dexamethasone (1 mg/kg) or vehicle were administered intranasally once daily 1h before each allergen challenge. On day 21, airway hyperresponsiveness, bronchoalveolar lavage inflammatory cells and Th2 cytokines, and lung tissue mucus and collagen were measured.ResultsAllergen challenge induced airway hyperresponsiveness in vehicle-treated animals as measured by whole body barometric plethysmography, and eosinophilia in bronchoalveolar lavage. POL7085 dose-dependently and significantly decreased airway hyperresponsiveness (34 ± 16 %) and eosinophil numbers in bronchoalveolar lavage (66 ± 6 %). In addition, the highest dose of POL7085 used significantly inhibited lung IL-4 (85 ± 4 %), IL-5 (87 ± 2 %) and IL-13 (190 ± 19 %) levels, and lung collagen (43 ± 11 %).ConclusionsThe Protein Epitope Mimetic CCR10 antagonist, POL7085, significantly and dose-dependently decreased allergen-induced airway hyperresponsiveness and airway inflammation after once daily local treatment. Our data give strong support for further investigations with CCR10 antagonists in asthmatic disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0231-5) contains supplementary material, which is available to authorized users.
Background: Trauma induces neutrophil migration toward injury sites, both initiating wound healing and protecting against local bacterial infection. We have previously shown that mitochondrial formyl peptides (mtFPs) released by injured tissues act as chemoattractants by ligating neutrophil (PMN) formyl peptide receptor 1 (FPR1). But this process can also internalize multiple neutrophil chemoattractant receptors and thus might limit neutrophil migration to the lung in response to bacteria. Our objective was to better understand susceptibility to pneumonia after injury and thus find ways to reverse it. Methods and Results: We modeled the alveolar chemotactic environment in pulmonary infections by incubating Staphylococcus aureus or Escherichia coli with peripheral blood mononuclear cells. Survey of the chemotactic mediators in the resultant conditioned media (CM) showed multiple potent chemoattractants. Pretreating PMN with mtFPs to mimic injury potently reduced net migration toward CM and this net effect was mostly reversed by an FPR1 antagonist. Using an established mouse model of injury-dependent lung infection, we then showed simple instillation of exogenous unstimulated human neutrophils into the airway resulted in bacterial clearance from the lung. Conclusion: Injury-derived mtFPs suppress global PMN localization into complex chemotactic environments like infected alveoli. Transplantation of naive exogenous human neutrophils into the airway circumvents that pathologic process and prevents development of post-traumatic pneumonia without injury noted to the recipients.
IntroductionAsthma is major health burden throughout the world, and there are no therapies that have been shown to be able to prevent the development of disease. A severe respiratory paramyxoviral infection early in life has been demonstrated to greatly increase the risk of developing asthma. We have a mouse model of a severe respiratory paramyxoviral infection (Sendai virus, SeV) that mimics human disease, and requires early expression of the cytokine CCL28 to drive the development of post‐viral airway disease. The known receptors for CCL28 are CCR3 and CCR10. However, it is not known if blockade of these receptors will prevent the development of post‐viral airway disease. The objective of this study was to determine if treatment with a protein epitope mimetic antagonist of CCR10, POL7085, will provide sufficient protection against the development of post‐viral airway disease.MethodsC57BL6 mice were inoculated with SeV or UV inactivated SeV. From day 3–19 post inoculation (PI), mice were subcutaneously administered daily POL7085 or saline, or every other day anti‐CCL28 mAb. On days 8, 10, and 12 PI bronchoalveolar cytokines, serum IgE, and lung cellular constituents were measured. At day 21 PI airway hyper‐reactivity to methacholine and mucous cell metaplasia was measured.ResultsTreatment with either anti‐CCL28 or POL7085 significantly reduced development of airway hyper‐reactivity and mucous cell metaplasia following SeV infection. The prevention of post‐viral airway disease was associated with early reductions in innate immune cells, but did not appear to be due to a reduction in IL‐13 or IgE.ConclusionsBlockade of CCL28 or CCR10 during an acute severe respiratory paramyxoviral infection is sufficient to prevent the development of post‐viral airway disease. However, the mechanism of action is unclear and requires further exploration.
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