Inflammatory mechanisms are proposed to play a significant role in the pathogenesis of pulmonary arterial hypertension (PAH). Previous studies have described PAH in fat-fed apolipoprotein E knockout (ApoE(-/-)) mice. We have reported that signaling in interleukin-1-receptor-knockout (IL-1R1(-/-)) mice leads to a reduction in diet-induced systemic atherosclerosis. We subsequently hypothesized that double-null (ApoE(-/-)/IL-1R1(-/-)) mice would show a reduced PAH phenotype compared with that of ApoE(-/-) mice. Male IL-1R1(-/-), ApoE(-/-), and ApoE(-/-)/IL-1R1(-/-) mice were fed regular chow or a high-fat diet (Paigen diet) for 8 weeks before phenotyping for PAH. No abnormal phenotype was observed in the IL-1R1(-/-) mice. Fat-fed ApoE(-/-) mice developed significantly increased right ventricular systolic pressure and substantial pulmonary vascular remodeling. Surprisingly, ApoE(-/-)/IL-1R1(-/-) mice showed an even more severe PAH phenotype. Further molecular investigation revealed the expression of a putative, alternatively primed IL-1R1 transcript expressed within the lungs but not aorta of ApoE(-/-)/IL-1R1(-/-) mice. Treatment of ApoE(-/-) and ApoE(-/-)/IL-1R1(-/-) mice with IL-1-receptor antagonist prevented progression of the PAH phenotype in both strains. Blocking IL-1 signaling may have beneficial effects in treating PAH, and alternative IL-1-receptor signaling in the lung may be important in driving PAH pathogenesis.
In addition to localized tissue injury, intestinal ischaemia-reperfusion (I/R) leads to remote organ damage, in particular to the lungs. Given that nitric oxide (NO) can attenuate I/R-induced tissue injury in many situations, this study evaluated the effects of the NO donor, FK409, on leukocyte adhesion in the microcirculation of the intestinal villus and also assessed pulmonary tissue damage after intestinal I/R injury. PVG rats were subjected to 30 min intestinal ischaemia and a sub-group of animals received the NO donor FK409 (10 mg/kg; i.v.) both 30 min prior to ischaemia and 30 min post-reperfusion. The intestinal mucosal surface was visualized via an incision made in an exteriorized ileal segment and leukocyte adhesion in the villous microcirculation was determined by in vivo microscopy. Total and differential leukocyte counts from peripheral blood were evaluated. Lungs were removed at the end for histological assessment. Six out of ten untreated I/R animals failed to survive the 2 h reperfusion period, whereas all ten FK409-treated animals survived. I/R induced a significant increase in villous leukocyte adhesion of untreated I/R animals (p<0.001) and this was significantly decreased by FK409 treatment (p<0.001). The total leukocyte count was significantly decreased in untreated I/R animals (p<0.001) and this primarily resulted from a reduction in circulating neutrophil numbers. This effect was not observed in FK409-treated animals. Collapsed alveoli, thickened interstitial walls, and a dense neutrophilic infiltrate were apparent in the lungs of untreated I/R animals, whereas lung histology was normal in FK409-treated animals. In conclusion, FK409 prevented mortality, significantly reduced villous leukocyte adhesion, maintained circulating leukocyte numbers, and prevented pulmonary tissue injury following intestinal I/R. FK409 may therefore be of value in reducing both local and remote tissue damage and improving outcome in situations where intestinal I/R injury is obligatory, such as small bowel transplantation.
Bone morphogenetic protein receptor type 2 (BMPR2) mutations are present in patients with heritable and idiopathic pulmonary arterial hypertension (PAH). Circulating levels of interleukin-1 (IL-1) are raised in patients and animal models. Whether interplay between BMP and IL-1 signaling can explain the local manifestation of PAH in the lung remains unclear. Cell culture, siRNA, and mRNA microarray analysis of RNA isolated from human pulmonary artery (PASMC) and aortic (AoSMC) smooth muscle cells were used. R899X+/– BMPR2 transgenic mice fed a Western diet for six weeks were given daily injections of IL-1ß prior to assessment for PAH and tissue collection. PASMC have reduced inflammatory activation in response to IL-1ß compared with AoSMCs; however, PASMC with reduced BMPR2 demonstrated an exaggerated response. Mice treated with IL-1ß had higher white blood cell counts and significantly raised serum protein levels of IL-6 and osteoprotegerin (OPG) plasma levels recapitulating in vitro data. Phenotypically, IL-1ß treated mice demonstrated increased pulmonary vascular remodeling. IL-1ß induces an exaggerated pulmonary artery specific transcriptomic inflammatory response when BMPR2 signaling is reduced.
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