Decreased CXCL12 is Associated with Impaired Alveolar Epithelial Cell Migration and Poor Lung Healing After Lung Resection

Overview

Journal Surgery

Specialty General Surgery

Date 2015 Jul 28

PMID 26212341

Citations 7

Authors

Jacob A Kanter

Haiying Sun

Stephen Chiu

Malcolm M DeCamp

Peter H S Sporn

Jacob I Sznajder

Ankit Bharat

Affiliations

Soon will be listed here.

Abstract

Background: Prolonged air leak (PAL) is an important cause of morbidity and mortality after lung resection, but its pathogenesis has not been elucidated. Migration of alveolar type II epithelial cells is essential for lung wound repair. Here we determined the role of C-X-C motif chemokine 12 (CXCL12) on alveolar epithelial cell migration and lung wound healing.

Methods: CXCL12 in the pleural fluid of patients was analyzed using enzyme-linked immunosorbent assay. Human A549 and murine MLE12 alveolar epithelial cell lines were used for wound closure, cell migration, and proliferation assays. Western blot was used to analyze Rac1 and cofilin.

Results: Pleural CXCL12 was decreased in patients with PAL (1,389 ± 192 vs 3,270 ± 247 pg/mL; P < .0001). CXCL12 enhanced scratch wound closure in both A549 (77.9 ± 0.7% vs 71.5 ± 0.4%; P = .0016) and MLE12 (92.9 ± 4.9% vs 66.0 ± 4.8%; P = .017). CXCL12 enhanced migration by 57% in A549 (P = .0008) and by 86% in MLE12 (P < .0001). AMD3100, a selective CXCR4 antagonist, prevented the effects of CXCL12. CXCL12 increased Rac1 and cofilin activation but did not change bromodeoxyuridine incorporation or cell counts.

Conclusion: Reduced pleural CXCL12 is associated with PAL. CXCL12 promotes alveolar epithelial cell migration by binding to its receptor CXCR4 and may have a role in lung healing. CXCL12-mediated alveolar epithelial cell migration is associated with Rac1 and cofilin activation.

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References

Coughlin S, Emmerton-Coughlin H, Malthaner R . Management of chest tubes after pulmonary resection: a systematic review and meta-analysis. Can J Surg. 2012; 55(4):264-70. PMC: 3404148. DOI: 10.1503/cjs.001411. View

DeCamp M, Blackstone E, Naunheim K, Krasna M, Wood D, Meli Y . Patient and surgical factors influencing air leak after lung volume reduction surgery: lessons learned from the National Emphysema Treatment Trial. Ann Thorac Surg. 2006; 82(1):197-206. DOI: 10.1016/j.athoracsur.2006.02.050. View

Ghosh M, Makena P, Gorantla V, Sinclair S, Waters C . CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2. Am J Physiol Lung Cell Mol Physiol. 2012; 302(9):L846-56. PMC: 3362158. DOI: 10.1152/ajplung.00321.2011. View

Abolhoda A, Liu D, Brooks A, Burt M . Prolonged air leak following radical upper lobectomy: an analysis of incidence and possible risk factors. Chest. 1998; 113(6):1507-10. DOI: 10.1378/chest.113.6.1507. View

Ratajczak M, Zuba-Surma E, Kucia M, Reca R, Wojakowski W, Ratajczak J . The pleiotropic effects of the SDF-1-CXCR4 axis in organogenesis, regeneration and tumorigenesis. Leukemia. 2006; 20(11):1915-24. DOI: 10.1038/sj.leu.2404357. View

Brunelli A, Monteverde M, Borri A, Salati M, Marasco R, Fianchini A . Predictors of prolonged air leak after pulmonary lobectomy. Ann Thorac Surg. 2004; 77(4):1205-10. DOI: 10.1016/j.athoracsur.2003.10.082. View

Wang N, Gates K, Trejo H, Favoreto Jr S, Schleimer R, Sznajder J . Elevated CO2 selectively inhibits interleukin-6 and tumor necrosis factor expression and decreases phagocytosis in the macrophage. FASEB J. 2010; 24(7):2178-90. PMC: 2887258. DOI: 10.1096/fj.09-136895. View

Gomez-Caro A, Roca Calvo M, Torres Lanzas J, Chau R, Cascales P, Parrilla P . The approach of fused fissures with fissureless technique decreases the incidence of persistent air leak after lobectomy. Eur J Cardiothorac Surg. 2006; 31(2):203-8. DOI: 10.1016/j.ejcts.2006.11.030. View

Lackey A, Mitchell J . The cost of air leak: physicians' and patients' perspectives. Thorac Surg Clin. 2010; 20(3):407-11. DOI: 10.1016/j.thorsurg.2010.04.004. View

10.

Cerfolio R, Tummala R, Holman W, Zorn G, Kirklin J, McGiffin D . A prospective algorithm for the management of air leaks after pulmonary resection. Ann Thorac Surg. 1999; 66(5):1726-31. DOI: 10.1016/s0003-4975(98)00958-8. View

11.

Martin C, Peters K, Behar S . Macrophages clean up: efferocytosis and microbial control. Curr Opin Microbiol. 2014; 17:17-23. PMC: 3942671. DOI: 10.1016/j.mib.2013.10.007. View

12.

Kryczek I, Wei S, Keller E, Liu R, Zou W . Stroma-derived factor (SDF-1/CXCL12) and human tumor pathogenesis. Am J Physiol Cell Physiol. 2006; 292(3):C987-95. DOI: 10.1152/ajpcell.00406.2006. View

13.

Kalatskaya I, Berchiche Y, Gravel S, Limberg B, Rosenbaum J, Heveker N . AMD3100 is a CXCR7 ligand with allosteric agonist properties. Mol Pharmacol. 2009; 75(5):1240-7. DOI: 10.1124/mol.108.053389. View

14.

Rafii S, Cao Z, Lis R, Siempos I, Chavez D, Shido K . Platelet-derived SDF-1 primes the pulmonary capillary vascular niche to drive lung alveolar regeneration. Nat Cell Biol. 2015; 17(2):123-136. PMC: 4886751. DOI: 10.1038/ncb3096. View

15.

Sanchez-Martin L, Sanchez-Mateos P, Cabanas C . CXCR7 impact on CXCL12 biology and disease. Trends Mol Med. 2012; 19(1):12-22. DOI: 10.1016/j.molmed.2012.10.004. View

16.

Sisson T, Mendez M, Choi K, Subbotina N, Courey A, Cunningham A . Targeted injury of type II alveolar epithelial cells induces pulmonary fibrosis. Am J Respir Crit Care Med. 2009; 181(3):254-63. PMC: 2817814. DOI: 10.1164/rccm.200810-1615OC. View

17.

Keller C . Lasers, staples, bovine pericardium, talc, glue and...suction cylinders? Tools of the trade to avoid air leaks in lung volume reduction surgery. Chest. 2004; 125(2):361-3. DOI: 10.1378/chest.125.2.361. View

18.

Mueller M, Marzluf B . The anticipation and management of air leaks and residual spaces post lung resection. J Thorac Dis. 2014; 6(3):271-84. PMC: 3949188. DOI: 10.3978/j.issn.2072-1439.2013.11.29. View

19.

Antanavicius G, Lamb J, Papasavas P, Caushaj P . Initial chest tube management after pulmonary resection. Am Surg. 2005; 71(5):416-9. View

20.

Xu J, Mora A, Shim H, Stecenko A, Brigham K, Rojas M . Role of the SDF-1/CXCR4 axis in the pathogenesis of lung injury and fibrosis. Am J Respir Cell Mol Biol. 2007; 37(3):291-9. PMC: 1994230. DOI: 10.1165/rcmb.2006-0187OC. View