The Journal of immunology : official journal of the American Association of Immunologists
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Matrix metalloproteinase-8 (MMP-8) is a potent interstitial collagenase thought to be expressed mainly by polymorphonuclear neutrophils. To determine whether MMP-8 regulates lung inflammatory or fibrotic responses to bleomycin, we delivered bleomycin by the intratracheal route to wild-type (WT) versus Mmp-8(-/-) mice and quantified MMP-8 expression, and inflammation and fibrosis in the lung samples. Mmp-8 steady state mRNA and protein levels increase in whole lung and bronchoalveolar lavage samples when WT mice are treated with bleomycin. ⋯ Studies of bleomycin-treated Mmp-8 bone marrow chimeric mice show that both leukocytes and lung parenchymal cells are sources of profibrotic MMP-8 during bleomycin-mediated lung fibrosis. Thus, during bleomycin-mediated lung injury, MMP-8 dampens the lung acute inflammatory response, but promotes lung fibrosis by reducing lung levels of IP-10 and MIP-1α. These data indicate therapeutic strategies to reduce lung levels of MMP-8 may limit fibroproliferative responses to injury in the human lung.
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The ability of the alveolar epithelium to prevent and resolve pulmonary edema is a crucial determinant of morbidity and mortality in acute lung injury (ALI). TNF has been implicated in ALI pathogenesis, but the precise mechanisms remain undetermined. We evaluated the role of TNF signaling in pulmonary edema formation in a clinically relevant mouse model of ALI induced by acid aspiration and investigated the effects of TNF p55 receptor deletion, caspase-8 inhibition, and alveolar macrophage depletion on alveolar epithelial function. ⋯ Caspase-8 inhibition significantly improved AFC and oxygenation, whereas depletion of alveolar macrophages attenuated epithelial dysfunction with reduced TNF production and caspase-8 activity. These results provide in vivo evidence for a novel role for TNF p55 receptor-mediated caspase-8 signaling, without substantial apoptotic cell death, in triggering alveolar epithelial dysfunction and determining the early pathophysiology of ALI. Blockade of TNF-induced death signaling may provide an effective early-phase strategy for ALI.
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Although acute or chronic inflammation is a common component of many clinical disorders, the underlying processes can be highly distinct. In recent years, the complement system has been associated with a growing number of immunological and inflammatory conditions that include degenerative diseases, cancer, and transplant rejection. ⋯ Although the exact involvement of complement needs to be carefully investigated for each disease, therapeutic modulation of complement activity emerges as an attractive target for upstream inhibition of inflammatory processes. This review provides an update about the functional and collaborative capabilities of complement, highlights major disease areas with known complement contribution, and indicates the potential for complement as a focal point in immunomodulatory strategies for treating inflammatory diseases.
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Asthma is a common inflammatory disease involving cross-talk between innate and adaptive immunity. We reveal that antibacterial innate immunity protein, peptidoglycan recognition protein (Pglyrp)1, is involved in the development of allergic asthma. Pglyrp1(-/-) mice developed less severe asthma than wild-type (WT) mice following sensitization with house dust mite (allergen) (HDM). ⋯ In vivo depletion of pDC in HDM-sensitized Pglyrp1(-/-) mice reversed the low responsive asthma phenotype of Pglyrp1(-/-) mice to resemble the more severe WT phenotype. Thus, Pglyrp1(-/-) mice efficiently control allergic asthma by upregulating pDC and Treg cells in the lungs, whereas in WT mice, Pglyrp1 is proinflammatory and decreases pDC and Treg cells and increases proasthmatic Th2 and Th17 responses. Blocking Pglyrp1 or enhancing pDC in the lungs may be beneficial for prevention and treatment of asthma.
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Expression of the cystic fibrosis transmembrane conductance regulator (CFTR) is altered in individuals with the ΔF508 CFTR mutation. We previously reported differential expression of microRNA (miRNA) in CF airway epithelium; however, the role of miRNA in regulation of CFTR expression here remains unexplored. In this study, we investigated the role of upregulated miRNAs in CFTR regulation in vivo in bronchial brushings from individuals homozygous or heterozygous for ΔF508 CFTR, validated our observations in vitro, and assessed the impact of defective chloride ion conductance, genotype, and colonization status on miRNA expression. miRNA target prediction was performed in silico, and expression of miRNA and target genes were measured by quantitative real-time PCR and/or Western blotting. ⋯ Reciprocal downregulation or upregulation of CFTR gene and/or protein expression was observed after miRNA manipulation and direct miRNA-target relationships demonstrated via a reporter system containing a wild type or mutated full-length CFTR 3' untranslated region. Increased expression of miR-145, miR-223, and miR-494 in vivo in bronchial epithelium of individuals carrying the ΔF508 CFTR mutation correlates with decreased CFTR expression. Defective CFTR function, Pseudomonas colonization, and inflammation may affect miRNA expression and contribute to the regulation of ΔF508 CFTR.