High-altitude hypoxia exacerbates dextran sulfate sodium (DSS)-induced colitis by upregulating Th1 and Th17 lymphocytes.

High altitude hypoxia (HAH) involves the pathogenesis of ulcerative colitis (UC) and gastrointestinal erosions. However, the mechanism of effects of HAH in colitis remains controversial. This study reports the immunomodulation mediated by HAH to enhancing the severity of UC in the mice model. BALB/c mice were used to establish the UC model by dextran sulfate sodium (DSS) compared to wild type mice. Mice groups were exposed to hypoxic conditions in a hypobaric chamber with an altitude of 5000 m for 7 days. Then, Spleen, mesenteric lymph nodes and colon tissues were collected. The activity of UC, the infiltration of the immune cells, and the released cytokines were investigated. Results showed that the severity of DSS-induced UC significantly increased in mice exposed to HAH. The analysis of pathological changes showed increased weight loss and decreased colon length accompanied by diarrhea and bloody feces in the hypobaric hypoxia group. Interestingly, the levels of inflammatory cytokines IL-17, TNF-α, and IFN-γ in the spleen and mesenteric lymph node showed a significant increase within the colon of the hypobaric hypoxia group. The population of Th 1 and Th 17 cells in the spleen was significantly increased in mice exposed to hypobaric hypoxia compared NC group. Suggesting that high altitude hypoxia enhances colitis in mice through activating the increase of inflammatory Th1 and Th17 lymphocytes. In conclusion, this study revealed that hypobaric hypoxia directly increases the severity of UC in the mice model via increasing the activity of inflammatory CD4+ Th1 and Th 17 lymphocytes.

Effects of hypoxic exposure on immune responses of intestinal mucosa to Citrobacter colitis in mice.

OBJECTIVE: The pathogenesis and mechanism of colitis may be related to intestinal flora, genetic susceptibility, environmental and immune factors. Among these various factors, the importance of environmental factors in the pathogenesis of colitis has been increasingly recognized. The purpose of this study was to investigate the effects of hypoxia on intestinal mucosal immunity. METHODS: Experimental colitis was induced by oral gavage of Citrobacter rodentium (C. rodentium) in mice, then divided into normoxia group and hypoxia group. Mice were sacrificed after 2 weeks. Physiological and blood biochemical indicators were monitored to verify the hypoxia model. The body weight, fecal bacterial output, colon length and colon histopathology were observed to evaluate severity of colitis. The concentration of cytokines in colonic tissues were detected by ELISA. The percentage of CD4+ IFN-γ+ (Th1) and CD4+ IL-17+ (Th17) cells in mesenteric lymph nodes (MLN) were detected by flow cytometry. The levels of mucosal antimicrobial peptides (AMPs), related inflammatory factors and transcription factors in colon tissues were detected by qRT-PCR. RESULTS: Mice in hypoxic C. rodentium infection (Hypoxia + C.r.) group exhibited significant decrease in body weight, increase in fecal bacterial pathogen output, and more severe histopathological damage in the colon compared with the C. rodentium infection (Nomoxia + C.r.) group. Meanwhile, the level of NF-κB, TLR4, COX-2, IL-6 and TNF-α of colonic tissue were increased, while IL17, IL-22, and Reg3γ were decreased. The percentage of CD4+ IFN-γ+ (Th1) and CD4+ IL-17+ (Th17) cells in MLN were significantly decreased in mice of Hypoxia + C.r. group, accompanied by the decreased of IFN-γ and IL-17. In addition, the level of the T-bet, RORγt, IL-12 and IL-23 were decreased in mice of Hypoxia + C.r. group. CONCLUSIONS: Hypoxic exposure significantly exacerbates the symptoms and the pathological damage of mice with colitis and influences the immune function by down-regulating Th1 and Th17 responses in C. rodentium-induced colitis in mice.

Effects of ß-adrenoceptor activation on haemodynamics during hypoxic stress in rats.

NEW FINDINGS: What is the central question of this study? The acute hypoxic compensatory reaction is based on haemodynamic changes, and ß-adrenoceptors are involved in haemodynamic regulation. What is the role of ß-adrenoceptors in haemodynamics during hypoxic exposure? What is the main finding and its importance? Activation of ß2 -adrenoceptors attenuates the increase in pulmonary artery pressure during hypoxic exposure. This compensatory reaction activated by ß2 -adrenoceptors during hypoxic stress is very important to maintain the activities of normal life. ABSTRACT: The acute hypoxic compensatory reaction is accompanied by haemodynamic changes. We monitored the haemodynamic changes in rats undergoing acute hypoxic stress and applied antagonists of ß-adrenoceptor (ß-ARs) subtypes to reveal the regulatory role of ß-ARs on haemodynamics. Sprague-Dawley rats were randomly divided into control, atenolol (ß1 -AR antagonist), ICI 118,551 (ß2 -AR antagonist) and propranolol (non-selective ß-AR antagonist) groups. Rats were continuously recorded for changes in haemodynamic indexes for 10 min after administration. Then, a hypoxic ventilation experiment [15% O2 , 2200 m a.sl., 582 mmHg (0.765 Pa), PO2 87.3 mmHg; Xining, China] was conducted, and the indexes were monitored for 5 min after induction of hypoxia. Plasma catecholamine concentrations were also measured. We found that, during normoxia, the mean arterial pressure, heart rate, ascending aortic blood flow and pulmonary artery pressure were reduced in the propranolol and atenolol groups. Catecholamine concentrations were increased significantly in the atenolol group compared with the control group. During hypoxia, mean arterial pressure and total peripheral resistance were decreased in the control, propranolol and ICI 118,551 groups. Pulmonary arterial pressure and pulmonary vascular resistance were increased in the propranolol and ICI 118,551 groups. During hypoxia, catecholamine concentrations were increased significantly in the control group, but decreased in ß-AR antagonist groups. In conclusion, the ß2 -AR is involved in regulation of pulmonary haemodynamics in the acute hypoxic compensatory reaction, and the activation of ß2 -ARs attenuates the increase in pulmonary arterial pressure during hypoxic stress. This compensatory reaction activated by ß2 -ARs during hypoxic stress is very important to maintain activities of normal life.