Rhodiola crenulata Extract Alleviates Hypoxic Pulmonary Edema in Rats

Abstract

Sudden exposure of nonacclimatized individuals to high altitude can easily lead to high altitude illnesses. High altitude pulmonary edema (HAPE) is the most lethal form of high altitude illness. The present study was designed to investigate the ability of Rhodiola crenulata extract (RCE), an herbal medicine traditionally used as an antiacute mountain sickness remedy, to attenuate hypoxia-induced pulmonary injury. Exposure of animals to hypobaric hypoxia led to a significant increase in pathological indicators for pulmonary edema, including the lung water content, disruption of the alveolar-capillary barrier, and protein-rich fluid in the lungs. In addition, hypobaric hypoxia also increased oxidative stress markers, including (ROS) production, (MDA) level, and (MPO) activity. Furthermore, overexpression of plasma (ET-1), (VEGF) in (BALF), and (HIF-1 α ) in lung tissue was also found. However, pretreatment with RCE relieved the HAPE findings by curtailing all of the hypoxia-induced lung injury parameters. These findings suggest that RCE confers effective protection for maintaining the integrity of the alveolar-capillary barrier by alleviating the elevated ET-1 and VEGF levels; it does so by reducing hypoxia-induced oxidative stress. Our results offer substantial evidence to support arguments in favor of traditional applications of Rhodiola crenulata for antihigh altitude illness.

Figure 1

RCE significantly attenuated hypoxia-induced pulmonary edema and alveolar extravascular protein. Effect of RCE on (a) W/D weight ratio and (b) BALF protein concentration. The rat control groups were treated with saline (control) or RCE under normoxia. The rat hypoxia groups received hypoxia treatment alone (H) or in combination with different doses of RCE (H + RCE). Results represent mean ± SEM (n = 6). *P < 0.05; **P < 0.01; ***P < 0.001 versus control; ^# P < 0.05; ^## P < 0.01; ^### P < 0.001  versus hypoxia (H).

Figure 2

Hypoxia exhibits no significant effect on the level of CINC-1. Results represent mean ± SEM (n = 6).

Figure 3

Effects of RCE on oxidative stress markers in lung tissue. RCE significantly attenuates (a) hypoxia-induced ROS bursts, (b) lipid peroxidation, and (c) the MPO activity in lung tissue. Results represent mean ± SEM (n = 6). *P < 0.05; **P < 0.01; ***P < 0.001 versus control; ^# P < 0.05; ^## P < 0.01; ^### P < 0.001 versus hypoxia (H).

Figure 4

RCE inhibited plasma ET-1, BALF VEGF, and HIF-1α expressions in hypoxia-treated animals. Hypoxia increased and RCE attenuated (a) plasma ET-1 level (n = 6), (b) BALF VEGF level (n = 6), and (c) HIF-1α protein expression level (n = 3). (d) Quantitative analysis of the relative level of HIF-1α from (c). Results represent mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 versus control; ^# P < 0.05; ^## P < 0.01; ^### P < 0.001  versus hypoxia (H).

Figure 5

Lung histology. Histological examination was performed by photomicrography (original magnification ×400). Exposure to hypoxia led to a disruption of the alveolar-capillary barrier as indicated by the arrow and congested vascular wall. Treatment with RCE maintained the integrity of the alveolar-capillary barrier from hypoxic insults. (a) Control, (b) RCE, 100 mg/kg, (c) hypoxia (H), (d) H + acetazolamide, 100 mg/kg, (e) H + RCE, 50 mg/kg, and (f) H + RCE, 100 mg/kg. Pictures depicted here represent three independent experiments.

Figure 6

The proposed mechanism of RCE for alleviating the pulmonary edema. RCE attenuates the hypoxia-induced alveolar-capillary barrier dysfunction by reducing oxidative stress.