Effects of acetazolamide on alveolar membrane permeability in rats under hypoxic stress

  Background  Acute exposed to high altitude areas can result in high altitude pulmonary edema (HAPE). Acetazolamide, as the internationally accepted drug of the first choice for the prevention of acute mountain sickness, has unclear regulatory effects in the process of hypoxic stress, especially its effect on alveolar membrane permeability.

  Objective  To observe the effect of acetazolamide on alveolar capillary membrane permeability in SD rats with acute hypoxia.

  Methods  Male SD rats were randomly divided into control group (CN group, Xining altitude 2260 m, n=12), hypoxia 7 km group (H7K group, simulated altitude of 7000 m, n=12), acetazolamide group (NAZ group, Xining altitude 2260 m, n=12), hypoxia and acetazolamide group (HAZ group, simulated altitude of 7000 m, n=12). NAZ group and HAZ group were given 1% acetazolamide (50 mg/kg). CN and H7K groups were given equal volume of 0.9% sodium chloride injection (45 mg/kg) twice a day for 5 days. The H7K and HAZ groups were placed in a low pressure simulation chamber in an altitude of 7000 m (Barometric pressure 305mmHg, PO₂ 63.7 mmHg) for 2 days. Arterial blood gas analysis was performed to measure arterial blood pH, partial pressure of carbon dioxide (PaCO₂), partial pressure of oxygen (PaO₂) and bicarbonate (HCO₃^-). The wet/dry weight ratio (W/D) of right lung tissue was determined. The contents of interleukin (IL-6) and tumor necrosis factor (TNF-α) in bronchoalveolar lavage fluid (BALF) and serum were tested. The mRNA expression levels of aquaporin 1 (AQP1) and aquaporin 5 (AQP5) in lung tissue were detected by qRT-PCR. The morphological and structural changes of lung tissues were compared, and the expression levels of AQP1 and AQP5 in lung tissues of rats in each group were detected by immunohistochemistry.

  Results  Compared with the CN group, the arterial blood pH and PaO₂ in NAZ group and H7K group decreased significantly (P < 0.05), while the W/D increased significantly (P < 0.05). The contents of IL-6 and TNF-α in BALF and serum increased, and AQP1, AQP5 mRNA and protein expressions in the right lung tissue of rats increased significantly (P < 0.05). HE staining showed that the alveolar epithelial cells in the H7K group were obviously swollen, and the alveolar septum was widened and exudated, suggesting interstitial edema. Compared with H7K group, arterial blood PaO₂ in HAZ group significantly increased (P < 0.05), while the W/D ratio decreased (P < 0.05). The contents of IL-6 in BALF, IL-6 and TNF-α in serum,and AQP1, AQP5 mRNA and protein expressions in the left lung tissues decreased (all P < 0.05). Lung tissue section staining showed occasional swelling of alveolar epithelial cells, slightly wider alveolar septum, and reduced pulmonary edema.

  Conclusion  Acetazolamide pretreatment can reduce the formation of inflammatory factors (IL-6 and TNF-α) and the expression of AQP1 and AQP5, inhibit the increase of alveolar membrane permeability under hypoxic stress, effectively relieve pulmonary edema and improve hypoxia.