Cardiopulmonary bypass increases pulmonary microvascular permeability through the Src kinase pathway: Involvement of caveolin-1 and vascular endothelial cadherin

Zhang,Junwen; Jiang,Zhaolei; Bao,Chunrong; Mei,Ju; Zhu,Jiaquan

doi:10.3892/mmr.2016.4831

Cardiopulmonary bypass increases pulmonary microvascular permeability through the Src kinase pathway: Involvement of caveolin-1 and vascular endothelial cadherin

Authors:
- Junwen Zhang
- Zhaolei Jiang
- Chunrong Bao
- Ju Mei
- Jiaquan Zhu
View Affiliations

Affiliations: Department of Cardiothoracic Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200092, P.R. China
Published online on: January 29, 2016 https://doi.org/10.3892/mmr.2016.4831
Pages: 2918-2924
Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Changes in pulmonary microvascular permeability following cardiopulmonary bypass (CPB) and the underlying mechanisms have not yet been established. Therefore, the aim of the present study was to elucidate the alterations in pulmonary microvascular permeability following CPB and the underlying mechanism. The pulmonary microvascular permeability was measured using Evans Blue dye (EBD) exclusion, and the neutrophil infiltration and proinflammatory cytokine secretion was investigated. In addition, the activation of Src kinase and the phosphorylation of caveolin‑1 and vascular endothelial cadherin (VE‑cadherin) was examined. The results revealed that CPB increased pulmonary microvascular leakage, neutrophil count and proinflammatory cytokines in the bronchoalveolar lavage fluid, and activated Src kinase. The administration of PP2, an inhibitor of Src kinase, decreased the activation of Src kinase and attenuated the increase in pulmonary microvascular permeability observed following CPB. Two important proteins associated with vascular permeability, caveolin‑1 and VE‑cadherin, were significantly activated at 24 h in the lung tissues following CPB, which correlated with the alterations in pulmonary microvascular permeability and Src kinase. PP2 administration inhibited their activation, suggesting that they are downstream factors of Src kinase activation. The data indicated that the Src kinase pathway increased pulmonary microvascular permeability following CPB, and the activation of caveolin‑1 and VE‑cadherin may be involved. Inhibition of this pathway may provide a potential therapy for acute lung injury following cardiac surgery.

View Figures

View References

1	Gibbon JH Jr: Application of a mechanical heart and lung apparatus to cardiac surgery. Minn Med. 37:171–185. 1954.PubMed/NCBI
2	Edmunds LH Jr: Advances in the heart-lung machine after John and Mary Gibbon. Ann Thorac Surg. 76:S2220–S2223. 2003. View Article : Google Scholar : PubMed/NCBI
3	Wahba A: Centrifugal blood pump use in routine cardiac surgery. Interact Cardiovasc Thorac Surg. 5:299–300. 2006. View Article : Google Scholar
4	Cox CS Jr, Allen SJ and Brennan MS: Analysis of intestinal microvascular permeability associated with cardiopulmonary bypass. J Surg Res. 83:19–26. 1999. View Article : Google Scholar : PubMed/NCBI
5	Ng CS, Wan S, Yim AP and Arifi AA: Pulmonary dysfunction after cardiac surgery. Chest. 121:1269–1277. 2002. View Article : Google Scholar : PubMed/NCBI
6	Serraf A, Aznag H, Baudet B, Détruit H, Séccatore F, Mazmanian MG and Planché C: Pulmonary vascular endothelial growth factor and nitric oxide interaction during total cardiopulmonary bypass in neonatal pigs. J Thorac Cardiovasc Surg. 125:1050–1057. 2003. View Article : Google Scholar : PubMed/NCBI
7	Okutani D, Lodyga M, Han B and Liu M: Src protein tyrosine kinase family and acute inflammatory responses. Am J Physiol Lung Cell Mol Physiol. 291:L129–L141. 2006. View Article : Google Scholar : PubMed/NCBI
8	Oyaizu T, Fung SY, Shiozaki A, Guan Z, Zhang Q, dos Santos CC, Han B, Mura M, Keshavjee S and Liu M: Src tyrosine kinase inhibition prevents pulmonary ischemia-reperfusion-induced acute lung injury. Intensive Care Med. 38:894–905. 2012. View Article : Google Scholar : PubMed/NCBI
9	Miyahara T, Hamanaka K, Weber DS, Drake DA, Anghelescu M and Parker JC: Phosphoinositide 3-kinase, Src and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs. Am J Physiol Lung Cell Mol Physiol. 293:L11–L21. 2007. View Article : Google Scholar : PubMed/NCBI
10	Liu YY, Li LF, Fu JY, Kao KC, Huang CC, Chien Y, Liao YW, Chiou SH and Chang YL: Induced pluripotent stem cell therapy ameliorates hyperoxia-augmented ventilator-induced lung injury through suppressing the Src pathway. PLoS One. 9:e1099532014. View Article : Google Scholar : PubMed/NCBI
11	Anderson RG: The caveolae membrane system. Annu Rev Biochem. 67:199–225. 1998. View Article : Google Scholar : PubMed/NCBI
12	Cohen A, Hnasko R, Schubert W and Lisanti MP: Role of caveolae and caveolins in health and disease. Physiol Rev. 84:1341–1379. 2004. View Article : Google Scholar : PubMed/NCBI
13	Minshall RD, Tiruppathi C, Vogel SM and Malik AB: Vesicle formation and trafficking in endothelial cells and regulation of endothelial barrier function. Histochem Cell Biol. 117:105–112. 2002. View Article : Google Scholar : PubMed/NCBI
14	Dejana E, Orsenigo F and Lampugnani MG: The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci. 121:2115–2122. 2008. View Article : Google Scholar : PubMed/NCBI
15	Orsenigo F, Giampietro C, Ferrari A, Corada M, Galaup A, Sigismund S, Ristagno G, Maddaluno L, Koh GY, Franco D, et al: Phosphorylation of VE-cadherin is modulated by haemodynamic forces and contributes to the regulation of vascular permeability in vivo. Nat Commun. 3:12082012. View Article : Google Scholar : PubMed/NCBI
16	Institute of Laboratory Animal Resources (US): Committee on Care, Use of Laboratory Animals, and National Institutes of Health (US). Division of Research Resources: Guide for the care and use of laboratory animals. 7th edition. National Academies Press; Washington, DC: 1996
17	Zhu J, Yin R, Shao H, Dong G, Luo L and Jing H: N-acetylcysteine to ameliorate acute renal injury in a rat cardiopulmonary bypass model. J Thorac Cardiovasc Surg. 133:696–703. 2007. View Article : Google Scholar : PubMed/NCBI
18	Cavriani G, Oliveira-Filho RM, Trezena AG, da Silva ZL, Domingos HV, de Arruda MJ, Jancar S and Tavares de Lima W: Lung microvascular permeability and neutrophil recruitment are differently regulated by nitric oxide in a rat model of intestinal ischemia-reperfusion. Eur J Pharmacol. 494:241–249. 2004. View Article : Google Scholar : PubMed/NCBI
19	Altmay E, Karaca P, Yurtseven N, Ozkul V, Aksoy T, Ozler A and Canik S: Continuous positive airway pressure does not improve lung function after cardiac surgery. Can J Anaesth. 53:919–925. 2006. View Article : Google Scholar : PubMed/NCBI
20	Apostolakis E, Filos KS, Koletsis E and Dougenis D: Lung dysfunction following cardiopulmonary bypass. J Card Surg. 25:47–55. 2010. View Article : Google Scholar
21	Engels M, Bilgic E, Pinto A, Vasquez E, Wollschläger L, Steinbrenner H, Kellermann K, Akhyari P, Lichtenberg A and Boeken U: A cardiopulmonary bypass with deep hypothermic circulatory arrest rat model for the investigation of the systemic inflammation response and induced organ damage. J Inflamm (Lond). 11:262014. View Article : Google Scholar
22	Macnaughton PD, Braude S, Hunter DN, Denison DM and Evans TW: Changes in lung function and pulmonary microvascular permeability after cardiopulmonary bypass. Crit Care Med. 20:1289–1294. 1992. View Article : Google Scholar : PubMed/NCBI
23	Messent M, Sinclair DG, Quinlan GJ, Mumby SE, Gutteridge JM and Evans TW: Pulmonary vascular permeability after cardiopulmonary bypass and its relationship to oxidative stress. Crit Care Med. 25:425–429. 1997. View Article : Google Scholar : PubMed/NCBI
24	Thomas SM and Brugge JS: Cellular functions regulated by Src family kinases. Annu Rev Cell Dev Biol. 13:513–609. 1997. View Article : Google Scholar : PubMed/NCBI
25	Kevil CG, Okayama N and Alexander JS: H(2)O(2)-mediated permeability II: Importance of tyrosine phosphatase and kinase activity. Am J Physiol Cell Physiol. 281:C1940–C1947. 2001.PubMed/NCBI
26	Nwariaku FE, Liu Z, Zhu X, Turnage RH, Sarosi GA and Terada LS: Tyrosine phosphorylation of vascular endothelial cadherin and the regulation of microvascular permeability. Surgery. 132:180–185. 2002. View Article : Google Scholar : PubMed/NCBI
27	Eliceiri BP, Paul R, Schwartzberg PL, Hood JD, Leng J and Cheresh DA: Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell. 4:915–924. 1999. View Article : Google Scholar
28	Paul R, Zhang ZG, Eliceiri BP, Jiang Q, Boccia AD, Zhang RL, Chopp M and Cheresh DA: Src deficiency or blockade of Src activity in mice provides cerebral protection following stroke. Nat Med. 7:222–227. 2001. View Article : Google Scholar : PubMed/NCBI
29	Tinsley JH, Ustinova EE, Xu W and Yuan SY: Src-dependent, neutrophil-mediated vascular hyperpermeability and beta-catenin modification. Am J Physiol Cell Physiol. 283:1745–1751. 2002. View Article : Google Scholar
30	Yuan SY: Protein kinase signaling in the modulation of microvascular permeability. Vascul Pharmacol. 39:213–223. 2002. View Article : Google Scholar
31	Eliceiri BP, Puente XS, Hood JD, Stupack DG, Schlaepfer DD, Huang XZ, Sheppard D and Cheresh DA: Src-mediated coupling of focal adhesion kinase to integrin alpha(v)beta5 in vascular endothelial growth factor signaling. J Cell Biol. 157:149–160. 2002. View Article : Google Scholar : PubMed/NCBI
32	Shi S, Garcia JG, Roy S, Parinandi NL and Natarajan V: Involvement of c-Src in diperoxovanadate-induced endothelial cell barrier dysfunction. Am J Physiol Lung Cell Mol Physiol. 279:L441–L451. 2000.PubMed/NCBI
33	Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, et al: Loss of caveolae, vascular dysfunction and pulmonary defects in caveolin-1 gene-disrupted mice. Science. 293:2449–2452. 2001. View Article : Google Scholar : PubMed/NCBI
34	Minshall RD, Sessa WC, Stan RV, Anderson RG and Malik AB: Caveolin regulation of endothelial function. Am J Physiol Lung Cell Mol Physiol. 285:L1179–L1183. 2003. View Article : Google Scholar : PubMed/NCBI
35	Gonzalez E, Nagiel A, Lin AJ, Golan DE and Michel T: Small interfering RNA-mediated down-regulation of caveolin-1 differentially modulates signaling pathways in endothelial cells. J Biol Chem. 279:40659–40669. 2004. View Article : Google Scholar : PubMed/NCBI
36	Sun Y, Hu G, Zhang X and Minshall RD: Phosphorylation of caveolin-1 regulates oxidant-induced pulmonary vascular permeability via paracellular and transcellular pathways. Circ Res. 105:676–685. 2009. View Article : Google Scholar : PubMed/NCBI
37	Shajahan AN, Timblin BK, Sandoval R, Tiruppathi C, Malik AB and Minshall RD: Role of Src-induced dynamin-2 phosphorylation in caveolae-mediated endocytosis in endothelial cells. J Biol Chem. 279:20392–20400. 2004. View Article : Google Scholar : PubMed/NCBI
38	Minshall RD, Tiruppathi C, Vogel SM, Niles WD, Gilchrist A, Hamm HE and Malik AB: Endothelial cell-surface gp60 activates vesicle formation and trafficking via Gi-coupled Src kinase signaling pathway. J Cell Biol. 150:1057–1070. 2000. View Article : Google Scholar : PubMed/NCBI
39	Hu G, Vogel SM, Schwartz DE, Malik AB and Minshall RD: Intercellular adhesion molecule-1-dependent neutrophil adhesion to endothelial cells induces caveolae-mediated pulmonary vascular hyperpermeability. Circ Res. 102:e120–e131. 2008. View Article : Google Scholar : PubMed/NCBI
40	Lim MJ, Chiang ET, Hechtman HB and Shepro D: Inflammation-induced subcellular redistribution of VE-cadherin, actin and gamma-catenin in cultured human lung microvessel endothelial cells. Microvasc Res. 62:366–382. 2001. View Article : Google Scholar : PubMed/NCBI
41	Gavard J, Hou X, Qu Y, Masedunskas A, Martin D, Weigert R, Li X and Gutkind JS: A role for a CXCR2/phosphatidylinositol 3-kinase gamma signaling axis in acute and chronic vascular permeability. Mol Cell Biol. 29:2469–2480. 2009. View Article : Google Scholar : PubMed/NCBI
42	Gavard J and Gutkind JS: VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol. 8:1223–1234. 2006. View Article : Google Scholar : PubMed/NCBI
43	Mehta D and Malik AB: Signaling mechanisms regulating endothelial permeability. Physiol Rev. 86:279–367. 2006. View Article : Google Scholar
44	Aberle H, Schwartz HR and Kemler R: Cadherin-catenin complex: Protein interactions and their implications for cadherin function. J Cell Biochem. 61:514–523. 1996. View Article : Google Scholar : PubMed/NCBI
45	Song L, Ge S and Pachter JS: Caveolin-1 regulates expression of junction-associated proteins in brain microvascular endothelial cells. Blood. 109:1515–1523. 2007. View Article : Google Scholar