Heat shock proteins (HSPs) can be induced by various stresses and play an important role in cell cycle progression. HSP70 has been shown to act as an inhibitor of apoptosis. We studied HSP70 expression in bronchial epithelial cells of C57BL/6 mice and homozygous HPS70 knockout mice (hsp70.1–/–) exposed to chronic hypoxic stress. We also investigated changes in cellular proliferation and apoptosis in relation to HSP70. Lungs were removed from mice after a three-week period of exposure to 10 % O2. Immunoblots for HSP70 and immunohistochemical staining for HSP70 and Ki-67 were performed. Apoptosis was assessed using the TUNEL assay. The three-week period of hypoxic stress did not change HSP70 levels in total lung tissue, but a significant reduction in HSP70 expression was observed in bronchiolar epithelial cells. In wild type mice, both HSP70 and Ki-67 expression were significantly reduced in bronchiolar epithelial cells. In homozygous HPS70 knockout mice (hsp70.1–/–), apoptosis of bronchiolar epithelial cells was significantly increased. Our results suggest that HSP70 may exert anti-apoptotic effects in mouse bronchiolar epithelial cells.
To determine whether changes in partial pressure of CO2 participate in mechanism enlarging the lung functional residual capacity (FRC) during chronic hypoxia, we measured FRC and ventilation in rats exposed either to poikilocapnic (group H, FIO2 0.1, FICO2 <0.01) or hypercapnic (group H+CO2, FIO2 0.1, FICO2 0.04-0.05) hypoxia for the three weeks and in the controls (group C) breathing air. At the end of exposure a body plethysmograph was used to measure ventilatory parameters (V´E, fR, VT) and FRC during air breathing and acute hypoxia (10 % O2 in N2). The exposure to hypoxia for three weeks increased FRC measured during air breathing in both experimental groups (H: 3.0±0.1 ml, H+CO2: 3.1±0.2 ml, C: 1.8±0.2 ml). During the following acute hypoxia, we observed a significant increase of FRC in the controls (3.2±0.2 ml) and in both experimental groups (H: 3.5±0.2 ml, H+CO2: 3.6±0.2 ml). Because chronic hypoxia combined with chronic hypercapnia and chronic poikilocapnic hypoxia induced the same increase of FRC, we conclude that hypercapnia did not participate in the FRC enlargement during chronic hypoxia., H. Maxová, M. Vízek., and Obsahuje bibliografii
We examined the effect of MCC-134, a novel inhibitor of mitochondrial ATP-sensitive K+ (mitoKATP) channels and activator of sarcolemmal ATP-sensitive K+ (sarcKATP) channels, on cardioprotection conferred by adaptation to chronic hypoxia. Adult male Wistar rats were exposed to intermittent hypobaric hypoxia (7000 m, 8 h/day, 5-6 weeks) and susceptibility of their hearts to ventricular arrhythmias and myocardial infarction was evaluated in anesthetized open-chest animals subjected to 20-min coronary artery occlusion and 3-h reperfusion on the day after the last hypoxic exposure. MCC-134 was administered intravenously 10 min before ischemia and 5 min before reperfusion in a total dose of 0.3 mg/kg or 3 mg/kg divided into two equal boluses. The infarct size (tetrazolium staining) was reduced from 59.2±4.4 % of the area at risk in normoxic controls to 43.2±3.3 % in the chronically hypoxic group. Chronic hypoxia decreased the reperfusion arrhythmia score from 2.4±0.5 in normoxic animals to 0.7±0.5. Both doses of MCC-134 completely abolished the antiarrhythmic protection (score 2.4±0.7 and 2.5±0.5, respectively) but only the high dose blocked the infarct size-limiting effect of chronic hypoxia (54.2±3.7 %). MCC-134 had no effect in the normoxic group. These results support the view that the opening of mitoKATP channels but not sarcKATP channels plays a crucial role in the mechanism by which chronic hypoxia improves cardiac tolerance to ischemia/reperfusion injury.
Effective protection of the heart against ischemia/reperfusion injury is one of the most important goals of experimental and clinical research in cardiology. Besides ischemic preconditioning as a powerful temporal protective phenomenon, adaptation to chronic hypoxia also increases cardiac tolerance to all major deleterious consequences of acute oxygen deprivation such as myocardial infarction, contractile dysfunction and ventricular arrhythmias. Although many factors have been proposed to play a potential role, the detailed mechanism of this long-term protection remains poorly understood. This review summarizes current limited eviden
ce for the involvement of ATP-sensitive potassium channels, reactive oxygen species, nitric oxide and various protein kinases in cardioprotective effects of chronic hypoxia.
We studied the role of the δ, µ, and к opioid receptor (OR)
subtypes in the cardioprotective effect of chronic continuous
normobaric hypoxia (CNH) in the model of acuteanoxia/
reoxygenation of isolated cardiomyocytes. Adaptation of rats to
CNH was performed by their exposure to atmosphere containing
12 % of O2 for 21 days. Anoxia/reoxygenation of cardiomyocytes
isolated from normoxic control rats caused the death of 51 % of
cells and lactate dehydrogenase (LDH) release. Adaptation of rats
to CNH resulted in the anoxia/reoxygenation-induced
cardiomyocyte death of only 38 %, and reduced the LDH release.
Pre-incubation of the cells with either the non-selective OR
blocker naloxone (300 nM/l), the δ OR antagonist TIPP(ψ)
(30 nM/l), the selective δ2 OR antagonist naltriben (1 nM/l) or the
μ OR antagonist CTAP (100 nM/l) for 25 minutes before anoxia
abolished the reduction of cell death and LDH release afforded by
CNH. The antagonist of δ1 OR BNTX (1 nM/l) or the κ OR
antagonist nor-binaltorphimine (3 nM/l) did not influence the
cytoprotective effects of CNH. Taken together, the cytoprotective
effect of CNH is associated with the activation of the δ2 and μ OR
localized on cardiomyocytes.
Exposure to chronic hypoxia results in hypoxic pulmonary hypertension characterized by structural remodeling of peripheral pulmonary vasculature. An important part of this remodeling is an increase of collagen turnover and deposition of newly formed collagen fibrils in the vascular walls. The activity of collagenolytic metalloproteinases in the lung tissue is notably increased in the first days of exposure to hypoxia. The increased collagenolytic activity results in the appearance of collagen cleavages, which may be implied in the triggering of mesenchymal proliferation in peripheral pulmonary arteries. We hypothesize that radical injury to pulmonary vascular walls is involved in collagenolytic metalloproteinase activation., J. Novotná, J. Herget., and Obsahuje bibliografii