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Activation of c-Src tyrosine kinase mediated the degradation of occludin in ventilator-induced lung injury.

Zhao T, Liu M, Gu C, Wang X, Wang Y - Respir. Res. (2014)

Bottom Line: HE staining and lung injury score showed more severe lung injury and alveolar edema in group H compared with group M and group C.For the in vitro study, occludin expression decreased and c-Src activation increased as indicated by the phosphorylation of c-Src over time.Mechanical ventilation can activate c-Src by phosphorylation and increase the degradation of occludin. c-Src inhibitor can ameliorate barrier function and lung injury by up-regulating occludin.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Jinan, 250014, Shandong Province, China. feishi_xin@126.com.

ABSTRACT

Background: Ventilator-induced lung injury (VILI) is characterized by increased alveolar permeability, pulmonary edema. The tyrosine kinase, c-Src, is involved in VILI but its role has not been fully elucidated. This study examined the relationship between c-Src activation and occludin levels in VILI both in vitro and in vivo.

Methods: For the in vivo study, Wistar rats were randomly divided into five groups: control (group C); normal tidal volume (group M); normal tidal volume + c-Src inhibitor (PP2) (group M + P); high tidal volume (group H); and high tidal volume + c-Src inhibitor (PP2) (group H + P). Rats in all groups but group C underwent mechanical ventilation for 4 h. For the in vitro study, MLE-12 cells pretreated with PP2 and siRNA underwent cyclic stretching at 8% or 20% for 0, 1, 2 and 4 h. The expressions of occludin, c-Src, and p-c-Src were analyzed by western blotting, hematoxylin and eosin (HE) staining, and immunofluorescence.

Results: For the in vivo study, rats in group H showed decreased occludin expression and activated c-Src compared with group C. HE staining and lung injury score showed more severe lung injury and alveolar edema in group H compared with group M and group C. Group H + P had less pulmonary edema induced by the high tidal volume ventilation. For the in vitro study, occludin expression decreased and c-Src activation increased as indicated by the phosphorylation of c-Src over time. Consistently, PP2 could restore occludin levels.

Conclusions: Mechanical ventilation can activate c-Src by phosphorylation and increase the degradation of occludin. c-Src inhibitor can ameliorate barrier function and lung injury by up-regulating occludin.

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Related in: MedlinePlus

Histological observation of lung injury in group C, group M, group M + P, group H and group H + P. Lung tissue sections were stained with hematoxylin-eosin (original magnification, ×200). One representative image for each of the lung microscopic photograph in the (A) group C, (B) group M, (C) group M + P, (D) group H, (E) group H + P, in three independent experiments is shown.
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Fig7: Histological observation of lung injury in group C, group M, group M + P, group H and group H + P. Lung tissue sections were stained with hematoxylin-eosin (original magnification, ×200). One representative image for each of the lung microscopic photograph in the (A) group C, (B) group M, (C) group M + P, (D) group H, (E) group H + P, in three independent experiments is shown.

Mentions: Mechanical ventilation increased the expression of total and phosphorylation c-Src and the degradation of occludin in group H (P < 0.05) compared with group C and M (Figure 6), as seen by western blotting. The expression of occludin was higher and c-Src level was lower in group H + P compared with group H (P < 0.05) (Figure 6). HE staining (Figure 7), lung injury score (Table 1) and W/D ratio (Table 2) showed that high tidal volume mechanical ventilation could cause alveolar congestion, infiltration or aggregation of neutrophils in the airspace or the vessel wall, and thickening of the alveolar wall. PP2 could ameliorate the lung injury. These results suggest that high tidal volume mechanical ventilation can activate c-Src and decrease occludin levels.Figure 6


Activation of c-Src tyrosine kinase mediated the degradation of occludin in ventilator-induced lung injury.

Zhao T, Liu M, Gu C, Wang X, Wang Y - Respir. Res. (2014)

Histological observation of lung injury in group C, group M, group M + P, group H and group H + P. Lung tissue sections were stained with hematoxylin-eosin (original magnification, ×200). One representative image for each of the lung microscopic photograph in the (A) group C, (B) group M, (C) group M + P, (D) group H, (E) group H + P, in three independent experiments is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4262993&req=5

Fig7: Histological observation of lung injury in group C, group M, group M + P, group H and group H + P. Lung tissue sections were stained with hematoxylin-eosin (original magnification, ×200). One representative image for each of the lung microscopic photograph in the (A) group C, (B) group M, (C) group M + P, (D) group H, (E) group H + P, in three independent experiments is shown.
Mentions: Mechanical ventilation increased the expression of total and phosphorylation c-Src and the degradation of occludin in group H (P < 0.05) compared with group C and M (Figure 6), as seen by western blotting. The expression of occludin was higher and c-Src level was lower in group H + P compared with group H (P < 0.05) (Figure 6). HE staining (Figure 7), lung injury score (Table 1) and W/D ratio (Table 2) showed that high tidal volume mechanical ventilation could cause alveolar congestion, infiltration or aggregation of neutrophils in the airspace or the vessel wall, and thickening of the alveolar wall. PP2 could ameliorate the lung injury. These results suggest that high tidal volume mechanical ventilation can activate c-Src and decrease occludin levels.Figure 6

Bottom Line: HE staining and lung injury score showed more severe lung injury and alveolar edema in group H compared with group M and group C.For the in vitro study, occludin expression decreased and c-Src activation increased as indicated by the phosphorylation of c-Src over time.Mechanical ventilation can activate c-Src by phosphorylation and increase the degradation of occludin. c-Src inhibitor can ameliorate barrier function and lung injury by up-regulating occludin.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology, Qianfoshan Hospital, Shandong University, No. 16766 Jingshi Road, Jinan, 250014, Shandong Province, China. feishi_xin@126.com.

ABSTRACT

Background: Ventilator-induced lung injury (VILI) is characterized by increased alveolar permeability, pulmonary edema. The tyrosine kinase, c-Src, is involved in VILI but its role has not been fully elucidated. This study examined the relationship between c-Src activation and occludin levels in VILI both in vitro and in vivo.

Methods: For the in vivo study, Wistar rats were randomly divided into five groups: control (group C); normal tidal volume (group M); normal tidal volume + c-Src inhibitor (PP2) (group M + P); high tidal volume (group H); and high tidal volume + c-Src inhibitor (PP2) (group H + P). Rats in all groups but group C underwent mechanical ventilation for 4 h. For the in vitro study, MLE-12 cells pretreated with PP2 and siRNA underwent cyclic stretching at 8% or 20% for 0, 1, 2 and 4 h. The expressions of occludin, c-Src, and p-c-Src were analyzed by western blotting, hematoxylin and eosin (HE) staining, and immunofluorescence.

Results: For the in vivo study, rats in group H showed decreased occludin expression and activated c-Src compared with group C. HE staining and lung injury score showed more severe lung injury and alveolar edema in group H compared with group M and group C. Group H + P had less pulmonary edema induced by the high tidal volume ventilation. For the in vitro study, occludin expression decreased and c-Src activation increased as indicated by the phosphorylation of c-Src over time. Consistently, PP2 could restore occludin levels.

Conclusions: Mechanical ventilation can activate c-Src by phosphorylation and increase the degradation of occludin. c-Src inhibitor can ameliorate barrier function and lung injury by up-regulating occludin.

Show MeSH
Related in: MedlinePlus