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Schistosoma mansoni eggs retained in host tissues induce innate cytokine release, contributing to the induction of Type-2 immune responses and granuloma formation, important to restrain cytotoxic antigens, but leading to fibrosis. Interleukin(IL)-33 participates in experimental models of inflammation and chemically induced fibrosis, but its role in S. mansoni-induced fibrosis is still unknown. To explore the role of the IL-33/suppressor of the tumorigenicity 2 (ST2) pathway, serum and liver cytokine levels, liver histopathology, and collagen deposition were comparatively evaluated in S. mansoni-infected wild-type (WT) and IL-33-receptor knockout (ST2−/−) BALB/c mice. Our data show similar egg counts and hydroxyproline in the livers of infected WT and ST2−/− mice; however, the extracellular matrix in ST2−/− granulomas was loose and disorganised. Pro-fibrotic cytokines, such as IL-13 and IL-17, and the tissue-repairing IL-22 were significantly lower in ST2−/− mice, especially in chronic schistosomiasis. ST2−/− mice also showed decreased α-smooth muscle actin (α-SMA) expression in granuloma cells, in addition to reduced Col III and Col VI mRNA levels and reticular fibres. Therefore, IL-33/ST2 signalling is essential for tissue repairing and myofibroblast activation during S. mansoni infection. Its disruption results in inappropriate granuloma organisation, partly due to the reduced type III and VI collagen and reticular fibre formation. [ABSTRACT FROM AUTHOR]

1 Bradykinin (BK) appears to play an important role in the developmental and maintenance of inflammation. Here, we assessed the role of the BK B[SUB2] receptor for the injuries that occur after ischemia and reperfusion (1/R) of the territory irrigated by the superior mesenteric artery. 2 Tissue (lung and duodenum) kallikrein activity increased after ischemia with greater enhancement after reperfusion. A selective inhibitor of tissue kallikrein. Phenylacetl-Phe-Ser-Arg.N-(2,3-dinitrophenyl)-ethylenediamine (TK1,0.001-10mgml[SUP-1]), inhibited kallikrein activity in a concentration-dependent manner in vitro. In vivo, pretreatment with TK1 (30 mg kg[SUP-1]) prevented the extravasation of plasma and the recruitment of neutrophils. 3 Similarly, the bradykinin B[SUB2] receptor antagonists, HOE 140 (1.01-1.0 mg kg[SUP-1]) or FR173657 (10.0mg kg[SUP-1]), inhibited reperfusion-induced increases in vascular permeability and the recruitment of neutrophils in the intestine and lungs. 4 In a model of more severe I/R injury, HOE 140 (1.0 mg kg[SUP-1]) inhibited the increase in vascular permeability, neutrophil recruitment, haemorrhage and tissue pathology. Furthermore, HOE 140 significantly inhibited-the elevations of TNF-α in tissue and serum and partially prevented lethality. This was associated with an increase in the concentrations of IL-10 in tissue and serum. 5 Thus, our results demonstrate that, following intestinal I/R injury, there is an increase in tissue kallikrein activity and activation of BK B[SUB2] receptors. B[SUB2] receptor activation is essential for the development of inflammatory tissue injury and lethality. These results contrast with those of others showing that BK mostly exerts a protective role during I/R injury. [ABSTRACT FROM AUTHOR]