Background: Aquaporins are channels permeable to water, and they are essential for immune cell migration. Results: We demonstrate that aquaporin-mediated water fluxes are necessary for the NLRP3 inflammasome-dependent release of mature IL-1 in vitro and in vivo. Conclusion: Aquaporins are implicated in the mechanisms of proinflammatory cytokine secretion during inflammation. Significance: The discovery of a new function for AQPs opens new diagnostic and therapeutic opportunities in inflammatory disorders.
Prostaglandin (PG) D 2 exerts contrasting activities in the inflamed lung via two receptors, the D prostanoid receptor (DP) and the chemoattractant receptor-homologous molecule expressed on T helper 2 lymphocytes. DP activation is known mainly to inhibit proinflammatory cell functions. We tested the effect of a DPspecific agonist, (4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid (BW245C), on pulmonary fibroblast functions in vitro and in a mouse model of lung fibrosis induced by bleomycin. DP mRNA expression was detected in cultured mouse lung primary fibroblasts and human fetal lung fibroblasts and found to be up-and down-regulated by interleukin-13 and transforming growth factor (TGF)-, respectively. Although micromolar concentrations of BW245C and PGD 2 did not affect mouse fibroblast collagen synthesis or differentiation in myofibroblasts, they both inhibited fibroblast basal and TGF--induced proliferation in vitro. The repeated administration of BW245C (500 nmol/kg body weight instilled transorally in the lungs 2 days before and three times per week for 3 weeks) in bleomycin-treated mice significantly decreased both inflammatory cell recruitment and collagen accumulation in the lung (21 days). Our results indicate that BW245C can reduce lung fibrosis in part via its activity on fibroblast proliferation and suggest that DP activation should be considered as a new therapeutic target in fibroproliferative lung diseases.
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