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[Research on the effect of protection against ventilator-induced lung injury via regulation of caveolin-1/heme oxygenase-1 signaling].

OBJECTIVE
To determine whether the inhibition of caveolin-1 tyrosine residues 14 (Cav-1-Y14) phosphorylation with protein tyrosine kinase inhibitors (PP2) will upregulate heme oxygenase-1 (HO-1) activity to protect against ventilation induced lung injury in vivo of an animal model.


METHODS
Fifty-four male Sprague-Dawley (SD) rats were randomly divided into nine groups (each n=6). Group A served as normal control group, in which rats did not receive ventilation but tracheotomy. Groups B1 and B2 received lung protective ventilation respectively for 1 hour or 2 hours. Groups C1 and C2 received high tidal volume (40 mL/kg) ventilation for 1 hour or 2 hours, respectively. The group D1 or D2 also received high tidal volume ventilation for 1 hour or 2 hour respectively, but they were given PP2 1 hour before high tidal volume ventilation. The groups E1 and E2 also received high tidal volume ventilation respectively for 1 hour or 2 hours, but tyrosine kinase inhibitor PP2 and HO-1 inhibitor zinc protoporphyrin IX (ZnPPIX) were given to animals 18 hours before high tidal volume ventilation. All the animals were sacrificed after ventilation, and the specimens of lung tissues and bronchoalveolar lavage fluid (BALF) were harvested. Then the changes in pathology of lung tissue was observed, and diffuse alveolar damage scores (DAD) were calculated, myeloperoxidase (MPO) activity was measured by colorimetric analysis, lung wet/dry ratio (W/D) was estimated. The expressions of phosphorylated caveolin-1 (P-Cav-1-Y14), caveolin-1 (Cav-1) and HO-1 were determined by Western Blot. The expressions of high mobility group B1 (HMGB1) and advanced glycation end product receptor (RAGE) in lung tissues were assayed with immunohistochemistry staining. The levels of tumor necrosis factor-α(TNF-α) in BALF were measured by enzyme linked immunosorbent assay (ELISA).


RESULTS
There was no significant difference in all the parameters between group A and groups B. Compared with group B1, DAD score, W/D ratio, the activity of MPO and the concentration of TNF-α in BALF in group C1 were significantly increased [ DAD score: 7.97±0.59 vs. 0.55±0.13, W/D ratio: 5.70±1.61 vs. 5.04±0.63, MPO (U/g): 1.82±0.14 vs. 0.77±0.26, TNF-α (ng/L): 370.10±29.61 vs. 54.38±8.18, all P<0.05], and the injury in ventilation 2 hours group was more serious than that in ventilation 1 hour group. Compared with groups C, all the parameters in groups D were significantly decreased. The parameters in groups E were significantly higher than those in groups A, B, and D, but no significant difference was found as compared with groups C. Compared with groups B, the protein expressions of Cav-1 and P-Cav-1-Y14 (gray value) in groups C were significantly increased (1 hour: 1.49±0.02 vs. 1.26±0.13, 1.34±0.02 vs. 0.87±0.04; 2 hours: 1.58±0.02 vs. 1.27±0.27, 1.31±0.01 vs. 0.95±0.02, all P<0.05), and the expression of HO-1 protein (gray value) was significantly decreased (1 hour: 0.59±0.02 vs. 1.10±0.01, 2 hours: 0.49±0.01 vs. 1.20±0.02, both P<0.05). No significant difference in Cav-1 protein expression between groups D as well as groups E and groups C. The protein expression of P-Cav-1-Y14 in groups D and E was significantly lower than that in groups C. The protein expression of HO-1 in groups D was significantly higher than that in groups C, but the phenomenon was not found in groups E as compared with groups C. Compared with group A, the positive expression of HMGB1 and RAGE in lung tissue in groups C and E was significantly increased, but no significant difference was found between groups B as well as groups D and group A.


CONCLUSIONS
Cav-1-Y14 phosphorylation is the key factor for ventilator induced lung injury, which can not only lead to a decrease in vascular barrier function, but also inhibit the activity of HO-1 enzyme, thus further aggravates inflammatory injury of the lung as induced by mechanical ventilation.