New insights of aquaporin 5 in the pathogenesis of high altitude pulmonary edema

Abstract

Background: High altitude pulmonary edema (HAPE) affects individuals and is characterized by alveolar flooding with protein-rich edema as a consequence of blood-gas barrier disruption. In this study, we hypothesized that aquaporin 5 (AQP5) which is one kind of water channels may play a role in preservation of alveolar epithelial barrier integrity in high altitude pulmonary edema (HAPE).

Methods: Therefore, we established a model in Wildtype mice and AQP5 -/- mice were assingned to normoxic rest (NR), hypoxic rest (HR) and hypoxic exercise (HE) group. Mice were produced by training to walk at treadmill for exercising and chamber pressure was reduced to simulate climbing an altitude of 5000 m for 48 hours. Studies using BAL in HAPE mice to demonstrated that edema is caused leakage of albumin proteins and red cells across the alveolarcapillary barrier in the absence of any evidence of inflammation.

Results: In this study, the Lung wet/dry weight ratio and broncholalveolar lavage protein concentrations were slightly increased in HE AQP5 -/- mice compared to wildtype mice. And histologic evidence of hemorrhagic pulmonary edema was distinctly shown in HE group. The lung Evan's blue permeability of HE group was showed slightly increased compare to the wildtype groups, and HR group was showed a medium situation from normal to HAPE development compared with NR and HE group.

Conclusions: Deletion of AQP5 slightly increased lung edema and lung injury compared to wildtype mice during HAPE development, which suggested that the AQP5 plays an important role in HAPE formation induced by high altitude simulation.

Figure 1

Survival curve. There were no significant differences between AQP5 −/− and wildtype p > 0.05. A: HE vs control between wildtype and AQP5 −/−, B: HE wildtype vs control wildtype, C: HE AQP5 −/− vs control AQP5 −/−, D: HE AQP5 −/− vs HE wildtype. Control wildtype, blue dotted line; Control AQP5 −/−, red dotted line; HE wildtype, blue full line; HE AQP5 −/−, red full line.

Figure 2

Lung wet-to-dry weight ratio. **p < 0.01 for the HE groups between AQP5 −/− and wildtype vs. controls; *p < 0.05 for the HR AQP5 −/− vs. the control. n = 6 in each group. Values are given as the mean ± SEM.

Figure 3

Protein content and cell counts in BAL. (A) Total protein. *p < 0.05 for the HE groups between AQP5 −/− and wildtype vs. controls. (B) Albumin. **p < 0.01 for the HE AQP5 −/− group vs. controls. *p < 0.05 for the HE wildtype group vs. controls. n = 6 in each group. Values are given as the mean ± SEM. (C) Red blood cell counts. * p < 0.05 for the HE groups between AQP5 −/− and wildtype vs. controls. (D) White blood cell counts. There were no significant differences within these groups. n = 3 in each group. Values are given as the mean ± SEM.

Figure 4

Lung histology in HAPE mice. Light micrograph of hematoxylin and eosin stained paraffin embedded section AQP5 −/− and wildtype vs. controls. The alveolar edema was shown by arrows. Magnification × 200 and × 400.

Figure 5

Alveolar-capillary permeability by Evan’s blue method. **p < 0.01 for the HE groups between AQP5 −/− and wildtype vs. HR and controls; &&p < 0.01 for the HR AQP5 −/− vs. HE and controls; &p < 0.05 for the HR wildtype vs. HE and controls. n = 3 in each group. Values are given as the mean ± SEM.