| In recent years, studies have suggested that chronic intermittent hypobaric hypoxia(CIHH) could show beneficial effects on human immune disorders. CIHH treatment could promote the stability of immune function in allergic disease and shown improving even curing effects on bronchial asthma in children, allergies dermatitis and autoimmune thyroiditis in adult. Studies from our laboratory showed that CIHH treatment cloud protect the immune function of rats against acute hypoxia, prevent collagen-induced arthritis in rats, reduce the inflammation reaction and slow the pathological damage. Both animal and human experiments have confirmed that CIHH treatment cloud play a role in regulating the immune function, and may show therapeutic and protective effects on immune related diseases.IgA nephropathy(IgAN) is the most common glomerular disease, which shows high incidence in Asia and Pacific. The morbidity of IgAN accounts for about 30% of primary glomerular diseases in China. The pathogenesis of IgAN has not been fully elucidated. The available evidences indicated that IgAN is associated with congenital or acquired immune dysregulation. In IgAN patients, the synthesis of IgA in mucosal of respiratory tract or gastrointestinal will increase when stimulated by viruses and bacteria. IgA or IgA containing immune complexes deposite in the mesangial region resulting in glomerular inflammatory injury and mesangial cell proliferation. IgAN is a typical chronic autoimmunity diseases. BAFF(B cell activating factor) and IL-4 levels are elevated which would accelerate the progression of IgAN.There is still no specific treatment for IgAN. The early intervention treatment is the focus of IgAN related research.This study aimed to investigate the effects of CIHH on IgAN and the mechanism by establishing IgAN animal models through physiological,pharmacological, morphological and molecular biology techniques. Our study consisted of three parts:(1) To establish IgAN model in rats. The function and morphological changes in kidney of the animals will be observed and the reliability and quality of the model will be evaluated.(2) To clarify the effects of simulating 5000 m high altitude CIHH treament on IgAN.(3) To investigate the effects of simulating 3000 m high altitude CIHH treament on IgAN.Part one Establishing IgAN model in rats.Objective: To establish and evaluate the reliability and quality of the IgAN model.Methods: Sixty adult male Wistar rats were randomly divided into the two groups: control group(Control, n = 30) and IgAN group(IgAN, n = 30).The rat IgAN model was established by administration of bovine serum albumin(BSA), castor oil, carbon tetrachloride(CCl4) and lipopolysaccharide(LPS). Immunogen BSA was intragastrically administered at 400 mg/kg once every two days for 8 consecutive weeks and 0.1 ml of CCl4 in 0.3 ml of castor oil was given once weekly for 8 weeks. At the 6th and 8th week, 0.05 mg of LPS(Sigma, USA) was injected through the tail vein. For the control group, 4ml/kg distilled water was used to replace the BSA, 0.4 ml of castor oi l was used to replace castor oil and CCl4, and saline was used to replace LPS. The administration methods were the same as in the model group.The urine biochemical indexes, serum IgA levels and the morphology changes in renal tissue will be observed by using ELISA and immunofluorescence staining method.Results: 1 Hematuria and proteinuria were observed in IgAN rats since week-4, and the blood urea nitrogen and creatinine levels were increased simultaneously. There was significant difference between Cotrol and IgAN rats in week-8(P <0.05). The clinical manifestations of IgAN rat is similar to that of human IgAN.2 The serum IgA levels in IgAN rats was increased and IgA immunofluorescence staining showed mesangial IgA deposition since week-4.There was significant difference between Cotrol and IgAN rats in week-8(P<0.05). The immune dysregulation of IgAN rat is similar to that of human IgAN.3 The mesangial cell proliferation and inflammatory changes were observed in IgAN rats since week-4 and double immunofluorescence staining showed significant mesangial cell proliferation in week-8. The pathological changes of renal tissue in IgAN rats were similar to that of human IgAN.Conclusion:The Clinical symptom, the pathological changes in renal tissue and the possible pathogenesis of IgAN rat is similar to that of human IgAN. The IgAN rat model is satisfactory. This model is consistent with experimental study, can provide a research platform for further study of pathogenesis and treatment of IgAN.Part two Study on the anti IgA nephropathy effects of simulating 5000 m high altitude chronic intermittent hypobaric hypoxiaObjective: To clarify the effects of simulating 5000 m high altitude CIHH treament on IgAN.Methods: Adult male Wistar rats were randomly divided into the four groups: control group(Control, n =18), CIHH treatment group(Control +CIHH, n = 18), IgA nephropathy group(IgAN, n = 18) and IgAN receiving CIHH treatment group(IgAN + CIHH, n = 18). IgAN model was established in group IgAN and group IgAN+CIHH rats. Control and Control+CIHH group were living in the same environment and receiving comparator drugs. After 8weeks, the quality IgAN model is confirm by corresponding detections. The rats in Control + CIHH and IgAN + CIHH group were exposed to hypoxia simulating 5000 m high altitude in a hypobaric chamber for 28 days, 6 hours each day. Rats in Control group and IgAN group were fed in normal oxygen environment. The observation index is the same as that in the first part. IgA deposition in renal tissue were detected by Western Blot analysis. The serum BAFF and IL-4 were measured with ELISA kit.Results: 1 Compared with the IgAN group, the urinary red blood cell count and urine protein of IgAN+ CIHH rats were significantly decreased after 4 weeks of 5000 m CIHH treatment(P <0.05), as well as serum creatinine and blood urea nitrogen levels(P < 0.05).2 Compared with the IgAN group, the serum IgA levels were significantly decreased in IgAN+ CIHH rats after 4 weeks of 5000 m CIHH treatment(P<0.05). The results of renal tissue IgA immunofluorescence and Western Blot showed a decrease of IgA deposition in glomerular mesangial region in IgAN+ CIHH rats(P <0.05).3 Compared with the IgAN group, the glomerular inflammatory changes were reduced, and the proliferation of mesangial cells was decreased by double immunofluorescence staining in IgAN+ CIHH rats.4 Compared with the IgAN group, the serum levels of BAFF were decreased in IgAN+ CIHH rats(P <0.05). But CIHH did not affect the elevated serum IL-4 levels(P>0.05).Conclusion:Simulating 5000 m high altitude CIHH treament showed anti IgAN effects inc luding relieving clinical symptoms, improving renal function and reducing the renal pathological damage. These effects may due to the CIHH induced BAFF decrease. Simulating 5000 m high altitude CIHH treament may regulate B cell immunity and decrease its the over activation.Part three Study on the anti IgA nephropathy effects of simulating3000 m high altitude chronic intermittent hypobaric hypoxiaObjective: To clarify the effects of simulating 3000 m high altitude CIHH treament on IgAN.Methods: The experimental groups were the same as those in Part 2. The rats in Control + CIHH and IgAN + CIHH group were exposed to hypoxia simulating 3000 m high altitude in a hypobaric chamber for 28 days, 5 hours each day. The observation index is the same as that in part 2.Results: 1 Compared with the IgAN group, the urinary red blood cell count and urine protein of IgAN+ CIHH rats were significantly decreased after4 weeks of 3000 m CIHH treatment(P <0.05), as well as serum creatinine and blood urea nitrogen levels(P < 0.05).2 Compared with the IgAN group, the serum IgA levels were significantly decreased in IgAN+ CIHH rats after 4 weeks of 3000 m CIHH treatment(P <0.05). The results of renal tissue IgA immunofluorescence and Western Blot showed a decrease of IgA deposition in glomerular mesangial region in IgAN+ CIHH rats(P <0.05).3 Compared with the IgAN group, the glomerular inflammatory changes were reduced, and the proliferation of mesangial cells was significantly decreased by double immunofluorescence staining in IgAN+ CIHH rats.4 Compared with the IgAN group, the serum levels of BAFF and IL-4were decreased in IgAN+ CIHH rats(P <0.05).Conclusion:Simulating 3000 m high altitude CIHH treament showed anti IgAN effects inc luding relieving clinical symptoms, improving renal function and reducing the renal pathological damage. These effects may due to the CIHH induced BAFF and IL-4 decrease. Simulating 3000 m high altitude CIHH treament may regulate B cell and T cell immunity, decrease the activation of B cell and in turn decrease IgA secretion. |
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