Increasing evidence has highlighted the role of tubule-interstitial injury (TII) as a vital step in the pathogenesis of acute kidney injury (AKI). Incomplete repair of TII during AKI could lead to the development of chronic kidney disease. Changes in albumin endocytosis in proximal tubule epithelial cells (PTECs) is linked to the development of TII. In this context, interleukin (IL)-4 has been shown to be an important factor in modulating recovery of TII. We have studied the possible role of IL-4 in TII induced by albumin overload. A subclinical AKI model characterized by albumin overload in the proximal tubule was used, without changing glomerular function. Four groups were generated: (1) CONT, wild-type mice treated with saline; (2) BSA, wild-type mice treated with 10 g/kg/day bovine serum albumin (BSA); (3) KO, IL4Rα −/− mice treated with saline; and (4) KO + BSA, IL4Rα −/− mice treated with BSA. As reported previously, mice in the BSA group developed TII without changes in glomerular function. The following parameters were increased in the KO + BSA group compared with the BSA group: (1) tubular injury score; (2) urinary γ-glutamyltransferase; (3) CD4 + T cells, dendritic cells, macrophages, and neutrophils are associated with increases in renal IL-6, IL-17, and transforming growth factor β. A decrease in M2-subtype macrophages associated with a decrease in collagen deposition was observed. Using LLC-PK1 cells, a model of PTECs, we observed that (1) these cells express IL-4 receptor α chain associated with activation of the JAK3/STAT6 pathway; (2) IL-4 alone did not change albumin endocytosis but did reverse the inhibitory effect of higher albumin concentration. This effect was abolished by JAK3 inhibitor. A further increase in urinary protein and creatinine levels was observed in the KO + BSA group compared with the BSA group, but not compared with the CONT group. These observations indicate that IL-4 has a protective role in the development of TII induced by albumin overload that is correlated with modulation of the proinflammatory response. We propose that megalin-mediated albumin endocytosis in PTECs could work as a sensor, transducer, and target during the genesis of TII.
Acute lung injury (ALI) models are characterized by neutrophil accumulation, tissue damage, alteration of the alveolar capillary membrane, and physiological dysfunction. Lipoxin A 4 (LXA 4 ) is an anti-inflammatory eicosanoid that was demonstrated to attenuate lipopolysaccharide-induced ALI. Experimental models of severe malaria can be associated with lung injury. However, to date, a putative effect of LXA 4 on malaria (M)-induced ALI has not been addressed. In this study, we evaluated whether LXA 4 exerts an effect on M-ALI. Male C57BL/6 mice were randomly assigned to the following five groups: noninfected; saline-treated Plasmodium berghei-infected; LXA 4 -pretreated P. berghei-infected (LXA 4 administered 1 h before infection and daily, from days 0 to 5 postinfection), LXA 4 -and LXA 4 receptor antagonist BOC-2-pretreated P. berghei-infected; and LXA 4posttreated P. berghei-infected (LXA 4 administered from days 3 to 5 postinfection). By day 6, pretreatment or posttreatment with LXA 4 ameliorate lung mechanic dysfunction reduced alveolar collapse, thickening and interstitial edema; impaired neutrophil accumulation in the pulmonary tissue and blood; and reduced the systemic production of CXCL1. Additionally, in vitro treatment with LXA 4 prevented neutrophils from migrating toward plasma collected from P. berghei-infected mice. LXA 4 also impaired neutrophil cytoskeleton remodeling by inhibiting F-actin polarization.Ex vivo analysis showed that neutrophils from pretreated and posttreated mice were unable to migrate. In conclusion, we demonstrated that LXA 4 exerted therapeutic effects in malariainduced ALI by inhibiting lung dysfunction, tissue injury, and neutrophil accumulation in lung as well as in peripheral blood. Furthermore, LXA 4 impaired the migratory ability of P. berghei-infected mice neutrophils. K E Y W O R D Scytoskeleton remodeling, lung, LXA 4 receptor, Plasmodium berghei, specialized proresolving mediators INTRODUCTIONMalaria is present in more than 100 countries and accounts for 438,000 deaths each year. 1,2 The most severe form of malaria is Abbreviations: ALI, acute lung injury; ALX/FPR, LXA 4 receptor/formyl peptide receptor; ARDS, acute respiratory distress syndrome; BOC-2, N-Boc-Phe-Leu-Phe-Leu-Phe; CC, C-C motif chemokine; DAD, diffuse alveolar damage; HPFs, high-power fields; LTB 4 , leukotriene B 4 ; LXA 4 , lipoxin A 4 ; MA-ARDS, malaria associated ARDS; M-ALI, malaria induced ALI; Nip, noninfected plasma; Pbp, Plasmodium berghei-infected mouse plasma; PbRBC, Plasmodium berghei parasitized red blood cell; PI, propidium iodide characterized by cerebral dysfunction, which can result in convulsions, long-term neurological deficits, coma, and death. 3,4 Additionally, malaria-associated acute respiratory distress syndrome (MA-ARDS) is a common complication of malaria in adults, and the prevalence of MA-ARDS ranges from 2% to more than 20% of adults with severe malaria, depending on the study area and parasite species. 5,6 Autopsies performed in fatal cases of severe cerebral malaria show l...
23Introduction. Platelets drive endothelial cell activation in many diseases. 24 However, if this occurs in Plasmodium vivax malaria is unclear. As platelets have 25 been reported to be activated and to play a role in inflammatory response during 26 malaria, we hypothesized that this would correlate with endothelial alterations 27 during acute illness. 28Methods. We performed platelet flow cytometry of PAC-1 and P-selectin. We 29 measured Platelet markers (CXCL4, CD40L, P-selectin, Thrombopoietin, IL-11) and 30 endothelial markers (ICAM-1, von Willebrand Factor and E-selectin) in plasma with a 31 multiplex-based assay. The values of each mediator were used to generate heatmaps, K-32 means clustering and Principal Component analysis. In addition, we determined pair-wise 33 Pearson's correlation coefficients to generate correlation networks. 34 Results. Platelet counts were reduced, and mean platelet volume increased in 35 malaria patients. The activation of circulating platelets in flow cytometry did not differ 36 between patients and controls. CD40L levels (Median [IQ]: 517 [406-651] vs. 1029 [732-37 1267] pg/mL, P=0.0001) were significantly higher in patients, while P-selectin (Median 38 [IQ]: 17.0 [15.4-20.6] vs. 22.2 [17.6-25.7] ng/mL, P=0.0621) and CXCL4 showed a 39 nonsignificant trend towards higher levels in patients. The network correlation 40 approach demonstrated the correlation between markers of platelet and endothelial 41 activation, and the heatmaps revealed a distinct pattern of activation in two subsets 42 of P. vivax patients when compared to controls.43 Conclusion. platelet activation occurs in uncomplicated vivax malaria and 44 this correlates with higher endothelial cell activation, especially in a subset of 45 patients. 46 47 131 (R&D Systems): CD40L, P-selectin, PF4 and thrombopoietin (TPO), IL-11, as 132 well as circulating markers of EC activation (ICAM-1, E-selectin, von Willebrand 133Factor (vWF)). We selected 31 patients for the multiplex assay from a wide range 134 of parasitemias (260 to 25,150 Pv-IE/μL), so that a wide spectrum of disease 135 burden could be evaluated. This subgroup did not differ from the overall 136 population of patients regarding severity of disease, sex proportion, platelet counts 137 and mean parasitemia. We selected nine controls matched for age and sex. For the 138 network analysis, we used some interpolated results from below standard range. 139 140
Zika virus (ZIKV) has the ability to cross placental and brain barriers, causing congenital malformations in neonates and neurological disorders in adults. However, the pathogenic mechanisms of ZIKV-induced neurological complications in adults and congenital malformations remain unknown. Gas6 is a soluble TAM receptor ligand able to promote flavivirus internalization and downregulation of immune responses. Here we demonstrate high Gas6 levels in the serum of patients with neurological complications which correlated with downregulation of genes associated with the type I IFN responses as consequence of Socs1 upregulation. Gas6 gamma-carboxylation is essential for ZIKV replication in monocytes, the main source of this protein. Gas6 also facilitates ZIKV replication in adult immunocompetent mice enabled susceptibility to transplacental infection and congenital malformations. Our data thus indicate that ZIKV promotes the upregulation of its ligand Gas6, which contributes to viral infectivity and drives the development of severe adverse outcomes during ZIKV infection.
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