Novel role for endogenous mitochondrial formylated peptide-driven formyl peptide receptor 1 signalling in acute respiratory distress syndrome.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is an often fatal neutrophil-dominant lung disease. Although influenced by multiple proinflammatory mediators, identification of suitable therapeutic candidates remains elusive. We aimed to delineate the presence of mitochondrial formylated peptides in ARDS and characterise the functional importance of formyl peptide receptor 1 (FPR1) signalling in sterile lung inflammation. METHODS: Mitochondrial formylated peptides were identified in bronchoalveolar lavage fluid (BALF) and serum of patients with ARDS by liquid chromatography-tandem mass spectrometry. In vitro, human neutrophils were stimulated with mitochondrial formylated peptides and their effects assessed by flow cytometry and chemotaxis assay. Mouse lung injury was induced by mitochondrial formylated peptides or hydrochloric acid. Bone marrow chimeras determined the contribution of myeloid and parenchymal FPR1 to sterile lung inflammation. RESULTS: Mitochondrial formylated peptides were elevated in BALF and serum from patients with ARDS. These peptides drove neutrophil activation and chemotaxis through FPR1-dependent mechanisms in vitro and in vivo. In mouse lung injury, inflammation was attenuated in Fpr1-/- mice, effects recapitulated by a pharmacological FPR1 antagonist even when administered after the onset of injury. FPR1 expression was present in alveolar epithelium and chimeric mice demonstrated that both myeloid and parenchymal FPR1 contributed to lung inflammation. CONCLUSIONS: We provide the first definitive evidence of mitochondrial formylated peptides in human disease and demonstrate them to be elevated in ARDS and important in a mouse model of lung injury. This work reveals mitochondrial formylated peptide FPR1 signalling as a key driver of sterile acute lung injury and a potential therapeutic target in ARDS

Children with vesicoureteric reflux have joint hypermobility and occasional tenascin XB sequence variants

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Sympathoimmune Anomalies Underlying the Response to Stressful Challenge in Human Immunodeficiency Virus Spectrum Disease

Objective: This study examined immune, endocrine, and cardiovascular reactivity during stressful behavioral challenge in human immunodeficiency virus (HIV) seropositive (HIV+) and seronegative (HIV-) men and women and assessed whether immunocellular reactivity was differentially associated with concomitant alterations in sympathetic response.Methods: The 133 HIV+ [84 asymptomatic, 49 symptomatic] and 92 HIV- subjects completed a speech stress reactivity protocol.Results: Immunocellular reactivity to the speech stressor did not differ among asymptomatic and symptomatic HIV+ groups; however, relative to seronegatives, reactivity differences were present. Specifically, HIV+ subjects exhibited greater increases in total number of T cells, as well as in cytotoxic/suppressor T cells, activated T cells, and activated cytotoxic/suppressor T cells, and less increase in natural killer (NK) cell numbers. In addition, less stress-induced increase in NK cell cytotoxicity was observed along with greater suppression of the lymphoproliferative response to mitogen stimulation in the HIV+ group. Although no group differences in catecholamine reactivity were observed, the association of immunoreactivity with catecholamine responsiveness differed between serostatus groups. Specifically, the HIV+ subjects compared with HIV- subjects displayed greater lymphocytosis per unit change in norepinephrine; whereas NK cell reactivity was positively related to epinephrine responsiveness, but only in the HIV- group. These findings were present even after controlling for age and body mass, as well as other potential influences on immunocellular migration, such as cortisol levels and prevailing cardiac output.Conclusion: Early in HIV spectrum disease, functional abnormalities in the stress-induced migratory ability of specific immunocellular subsets are present that may reflect an underlying pathophysiological alteration in sympathoimmune communication