In vivo and in vitro studies have clearly demonstrated that signaling mediated by the interaction of CD200 and its cognate receptor, CD200R, results in an attenuation of inflammatory or autoimmune responses through multiple mechanisms. The present results have shown a differential expression of CD200 in the respiratory tract of intact rats. Along the respiratory passage, CD200 was specifically distributed at the bronchiolar epithelia with intense CD200 immunoreactivity localized at the apical surface of some ciliated epithelial cells; only a limited expression was detected on the Clara cells extending into the alveolar duct. In the alveolar septum, double immunofluorescence showed intense CD200 immunolabeling on the capillary endothelia. A moderate CD200 labeling was observed on the alveolar type II epithelial cells. It was, however, absent in the alveolar type I epithelial cells and the alveolar macrophages. Immunoelectron microscopic study has revealed a specific distribution of CD200 on the luminal front of the thin portion of alveolar endothelia. During endotoxemia, the injured lungs showed a dose-and time-dependent decline of CD200 expression accompanied by a vigorous infiltration of immune cells, some of them expressing ionized calcium binding adapter protein 1 or CD200. Ultrastructural examination further showed that the marked reduction of CD200 expression was mainly attributable to the loss of alveolar endothelial CD200. It is therefore suggested that CD200 expressed by different lung cells may play diverse roles in immune homeostasis of normal lung, in particular, the molecules on alveolar endothelia that may control regular recruitment of immune cells via CD200-CD200R interaction. Additionally, it may contribute to intense infiltration of immune cells following the loss or inefficiency of CD200 under pathological conditions.
CD200 belongs to cell adhesion molecules of the immunoglobulin superfamily. It lacks intracellular signaling motifs and exerts immunosuppressive effect in various tissues. We have reported previously that CD200 is predominantly associated with the capillary network in the alveolar septum of adult rats. The alveolar endothelial cells express CD200, which is confined to their luminal cell membrane facing the blood-air barrier. Our present results show that lung CD200 protein increases gradually with advancing age, being maximally expressed in the early postnatal (P) period. CD200 protein expression, however, declines at P5 but increases again after P7, reaching the adult level at P21. In developing lungs in fetal and neonatal stages, double-immunofluorescence staining has confirmed intense CD200 immunoreactivity delineating the vascular profiles in the double layers of the alveolar capillaries; this staining becomes diffuse and patchy with time. Unlike in adult lungs, immunoelectron microscopy has revealed that CD200 expression in fetal and early postnatal lungs is localized over the entire luminal cell membrane and in the cytoplasm of the endothelia. CD200 expression is progressively redistributed to a specific luminal domain of alveolar endothelia during pulmonary microvascular maturation. In neonatal rats treated with dexamethasone, the amount of lung CD200 significantly increases and is also elevated with time. Upregulation of endothelial CD200 has further been confirmed in isolated pulmonary microvascular endothelial cells treated with dexamethasone. Thus, lung CD200 is developmentally regulated, possibly under hormonal influence.
Backgrounds: Aristolochic acids is a nephrotoxic compounds found in some Chinese herbal medicine which induces aristolochic acids‐induced nephropathy (AAN). This study aimed to investigate the role of PPARα□and it mediated lipid metabolism in AAN. Materials and Methods: In vivo, mice were intreperitoneally injected with AA 5 mg/kg for continuous five days to induce AAN. Clofibrate (150 mg/kg) and statin (1 mg/kg) were administrated by gavage for two weeks before AA injection. Kidney injury and renal function changes were observed in AAN mice. The gene expression related to lipid metabolism as well as inflammation, fibrosis and cell death in the kidney of AAN mice were analyzed by RT‐PCR and western blot. In vitro, PPARα□and cellular lipid regulating gene changes in rat renal tubular (NRK52E) cell were analyzed under AA stimulation with or without PPARα□agonists including clofibrate, fenofibrate and OEA treatment. The protective effects of statin or clofibrate on cell viability were determined by MTT and LDH assays. The biomarkers for renal damage such as BMP‐7, Bcl‐xL, caspase 3 and connexin 43 were also analyzed. Results: In the AA‐injected mice, clofibrate, but not statin, improved the renal function and increase the renal PPARα expression. Clofibrate recovered the expression of lipid metabolism‐related genes such as adipocyte protein 2(aP2), lipoprotein lipase(LpL), CD36, fatty acid synthase(FAS) and ApoE in the kidney of mice which decreased by AA treatment. In addition, clofibrate treatment decreased inflammatory genes, TNF‐α, IL‐1β, MCP‐1, iNOS, Cox‐1 and Cox‐2 in the kidney of AAN mice. Moreover, clofibrate increased renal expression of BMP‐7, Bcl‐xL and connexin 43 expression while reduced TGF‐β, collagen IV, fibronectin, RAGE and caspase 3 in AAN mice. In AA‐stimulated NRK52Es, PPARα agonists prevented AA‐induced renal cell death, inflammation and abnormality of lipid metabolism. The renal protective effect of PPARα in NRK52E cell was blocked by treating with PPARα antagonist, MK886. Conclusion: Clofibrate could attenuates aristolochic acid nephropathy by increasing PPARα activity and it mediated lipid metabolism.
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