Advertisement

Effects of Tec Tyrosine Kinase Inhibition on the Inflammatory Response of Severe Acute Pancreatitis-Associated Acute Lung Injury in Mice

  • Yiteng Meng
  • Shuo Sha
  • Jing Yang
  • Hongbo RenEmail author
Original Article

Abstract

Background

The Tec kinase family is involved in acute and chronic inflammatory diseases, but its relationship with severe acute pancreatitis (SAP) remains unclear.

Aims

To investigate whether Tec tyrosine kinase can be used as a target for severe acute pancreatitis-associated acute lung injury (PALI).

Methods

A total of 90 mice were randomly assigned into four groups: SAP (n = 15), control (n = 15), SAP + α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide (LFM-A13) (pretreated with Tec kinase inhibitor LFM-A13, n = 15), and SAP + Tec siRNA (pretreated with PBS/negative control siRNA/Tec siRNA, n = 45). SAP was induced by caerulein and lipopolysaccharide. Animals were sacrificed at 0, 3, 24, 48, and 72 h, respectively. Pathological changes and scores of the lung and pancreas were determined using hematoxylin–eosin staining. Expression of Tec and phosphorylated Tec (p-Tec) were examined by real-time polymerase chain reaction, Western blot, and immunoprecipitation. Serum levels of amylase, myeloperoxidase, and pro-inflammatory cytokines were measured by ELISA.

Results

The expression of Tec in lung tissue was significantly higher in the SAP group than in the control group (p < 0.05), and p-Tec expression gradually increased with time. Furthermore, p-Tec expression was significantly lower in the SAP + LFM-A13 group than in the SAP group (p < 0.05); however, Tec expression did not vary. Tec inhibitors, LFM-A13 and Tec siRNA, alleviated pathological damage and release of inflammatory cytokines (p < 0.05).

Conclusions

Tec tyrosine kinase plays a key role in PALI, and is therefore a potential target for clinical treatment.

Keywords

Tec tyrosine kinase Severe acute pancreatitis Acute lung injury LFM-A13 siRNA 

Notes

Acknowledgments

This study was supported by the National Natural Science Foundation of China (No. 81470882). I would like to express many thanks to my classmate Shuo Sha and she contributed equally to this work. At the same time, Prof. Yan Zhang in Changhai Hospital of the Second Military Medical University and Peiyu Han in Jiang Nan University also help me a lot during the experiment.

Author’s contribution

Hongbo Ren designed the research. Yiteng Meng participated in animal experiments and wrote the paper. Shuo Sha and Jing Yang performed research and analyzed data.

Funding

This study was supported by the National Natural Science Foundation of China (No. 81470882).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

The present study was approved by the Research Ethics Committee of Qilu Hospital of Shandong University (KYLL-2014(KS)-050).

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

References

  1. 1.
    Forsmark CE, Vege SS, MelWilcox C. Acute pancreatitis. N Engl J Med. 2016;375:1972–1981.CrossRefGoogle Scholar
  2. 2.
    Zhu Y, Pan X, et al. Study on the etiology, severity, and mortality of 3260 patients with acute pancreatitis according to the revised Atlanta classification in Jiangxi, China Over an 8-year period. Pancreas. 2017;46:504–509.CrossRefGoogle Scholar
  3. 3.
    Das S, Mahakkanukrauh P, Ho CC. The burden of gastrointestinal, liver, and pancreatic diseases: the global scenario. Gastroenterology. 2016;150:1045–1046.CrossRefGoogle Scholar
  4. 4.
    Lankisch PG, Apte m, Banks PA. Acute pancreatitis. Lancet. 2015;386:85–96.CrossRefGoogle Scholar
  5. 5.
    Elder AS, Saccone GT, Dixon DL. Lung injury in acute pancreatitis: mechanisms underlying augmented secondary injury. Pancreatology. 2012;1:49–56.CrossRefGoogle Scholar
  6. 6.
    De Campos T, Deree J, Coimbra R. From acute pancreatitis to end organ injury: mechanisms of acute lung injury. Surg Infect (Larchmt). 2007;8:107–120.CrossRefGoogle Scholar
  7. 7.
    Dombernowsky T, Kristensen MØ, Rysgaard S, Gluud LL, Novovic S. Risk factors for and impact of respiratory failure on mortality in the early phase of acute pancreatitis. Pancreatology. 2016;16:756–760.CrossRefGoogle Scholar
  8. 8.
    Fanelli V, Ranieri VM. Mechanisms and clinical consequences of acute lung injury. Ann Am Thorac Soc. 2015;12:S3–S8.CrossRefGoogle Scholar
  9. 9.
    Wei M, Gong YJ, Tu L, et al. Expression of phosphatidylinositol-3 kinase and effects of inhibitor Wortmannin on expression of tumor necrosis factor-α in severe acute pancreatitis associated with acute lung injury. World J Emerg Med. 2015;6:299–304.CrossRefGoogle Scholar
  10. 10.
    Lei H, Minghao W, Xiaonan Y, et al. Acute lung injury in patients with severe acute pancreatitis. Turk J Gastroenterol. 2013;24:502–507.CrossRefGoogle Scholar
  11. 11.
    Maybauer MO, Maybauer DM, Herndon DN. Incidence and outcomes of acute lung injury. N Engl J Med. 2006;354:416–417.CrossRefGoogle Scholar
  12. 12.
    Milberg JA, Davis DR, Steinberg KP, Hudson LD. Improved survival of patients with acute respiratory distress syndrome (ARDS):1983–1993. JAMA. 1995;273:306–309.CrossRefGoogle Scholar
  13. 13.
    Vege SS, DiMagno MJ, Forsmark CE, Martel M, Barkun AN. Initial medical treatment of acute pancreatitis: american gastroenterological association institute technical review. Gastroenterology. 2018;154:1103–1139.CrossRefGoogle Scholar
  14. 14.
    Pezzilli R, Bellacosa L, Felicani C. Lung injury in acute pancreatitis. JOP. 2009;10:481–484.Google Scholar
  15. 15.
    Miller AT, Berg LJ. New insights into the regulation and functions of Tec family tyrosine kinases in the immune system. Curr Opin Immunol. 2002;14:331–340.CrossRefGoogle Scholar
  16. 16.
    Yang Wen-Chin, Collette Yves, Nune Jacques A, Olive Daniel. Tec Kinases: a Family Review with Multiple Roles in Immunity. Immunity.. 2000;12:373–382.CrossRefGoogle Scholar
  17. 17.
    Horwood NJ, Urbaniak AM, Danks L. Tec family kinases in inflammation and disease. Int Rev Immunol. 2012;31:87–103.CrossRefGoogle Scholar
  18. 18.
    Schmidt U, Boucheron N, Unger B, Ellmeier W. The role of tec family kinases in myeloid cells. Int Arch Allergy Immunol. 2004;134:65–78.CrossRefGoogle Scholar
  19. 19.
    Zemans RL, Arndt PG. Tec kinases regulate actin assembly and cytokine expression in LPS-stimulated human neutrophils via JNK activation. Cell Immunol. 2009;258:90–97.CrossRefGoogle Scholar
  20. 20.
    Wang F, Zhang W, Wang C, et al. Inhibitor of Tec kinase, LFM-A13, decreases pro-inflammatory mediators production in LPS-stimulated RAW264.7 macrophages via NF-κB pathway. Oncotarget. 2017;8:34099–34110.Google Scholar
  21. 21.
    Zhou MT, Chen CS, Chen BC, Zhang QY, Andersson R. Acute lung injury and ARDS in acute pancreatitis: mechanisms and potential intervention. World J Gastroenterol. 2010;16:2094–2099.CrossRefGoogle Scholar
  22. 22.
    Habtezion A. Inflammation in acute and chronic pancreatitis. Curr Opin Gastroenterol. 2015;31:395–399.CrossRefGoogle Scholar
  23. 23.
    Abdulla A, Awla D, Thorlacius H, Regnér S. Role of neutrophils in the activation of trypsinogen in severe acute pancreatitis. J Leukoc Biol. 2011;90:975–982.CrossRefGoogle Scholar
  24. 24.
    Montecucco F, Mach F, Lenglet S, et al. Treatment with Evasin-3 abrogates neutrophil-mediated inflammation in mouse acute pancreatitis. Eur J Clin Invest. 2014;44:940–950.CrossRefGoogle Scholar
  25. 25.
    Yu QH, Guo JF, Chen Y, et al. Captopril pretreatment protects the lung against severe acute pancreatitis induced injury via inhibiting angiotensin II production and suppressing Rho/ROCK pathway. Kaohsiung J Med Sci. 2016;32:439–445.CrossRefGoogle Scholar
  26. 26.
    Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome. J Pathol. 2004;202:145–156.CrossRefGoogle Scholar
  27. 27.
    Chen Y, Wang L, Kang Q, et al. Heat shock protein A12B protects vascular endothelial cells against sepsis-induced acute lung injury in mice. Cell Physiol Biochem. 2017;42:156–168.CrossRefGoogle Scholar
  28. 28.
    Seki H, Tasaka S, Fukunaga K, et al. Effect of Toll-like receptor 4 inhibitor on LPS-induced lung injury. Inflamm Res. 2010;59:837–845.CrossRefGoogle Scholar
  29. 29.
    Elder AS, Saccone GT,  Bersten AD, Dixon DL. Evaluation of lung injury and respiratory mechanics in a rat model of acute pancreatitiscomplicated with endotoxin. Pancreatology. 2012;12:240–247.CrossRefGoogle Scholar
  30. 30.
    Lerch MM, Gorelick FS. Models of acute and chronic pancreatitis. Gastroenterology. 2013;144:1180–1193.CrossRefGoogle Scholar
  31. 31.
    Ding SP, Li JC, Jin C. A mouse model of severe acute pancreatitis induced with caerulein and lipopolysaccharide. World J Gastroenterol. 2003;9:584–589.CrossRefGoogle Scholar
  32. 32.
    Uckun FM, Dibirdik I, Qazi S, et al. Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK). Bioorg Med Chem. 2007;15:800–814.CrossRefGoogle Scholar
  33. 33.
    Shen W, Gan J, Xu S, Jiang G, Wu H. Penehyclidine hydrochloride attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway. Pharmacol Res. 2009;60:296–302.CrossRefGoogle Scholar
  34. 34.
    Liu Y, Zhou D, Long FW, et al. Resolvin D1 protects against inflammation in experimental acute pancreatitis and associated lung injury. Am J Physiol Gastrointest Liver Physiol. 2016;310:G303–G309.CrossRefGoogle Scholar
  35. 35.
    Tampella G, Kerns HM, Niu D, et al. The Tec kinase-regulated phosphoproteome reveals a mechanism for the regulation of inhibitory signals in murine macrophages. J Immunol. 2015;195:246–256.CrossRefGoogle Scholar
  36. 36.
    Muhs BE, Patel S, Yee H, Marcus S, Shamamian P. Inhibition of matrix metalloproteinases reduces local and distant organ injury following experimental acute pancreatitis. J Surg Res. 2003;109:110–117.CrossRefGoogle Scholar
  37. 37.
    Luan ZG, Zhang XJ, Yin XH, et al. Downregulation of HMGB1 protects against the development of acute lung injury after severe acute pancreatitis. Immunobiology. 2013;218:1261–1270.CrossRefGoogle Scholar
  38. 38.
    Popa-Nita O, Marois L, Paré G, Naccache PH. Crystalinduced neutrophil activation:X. Proinflammatory role of the tyrosine kinase Tec. Arthritis Rheum. 2008;58:1866–1876.CrossRefGoogle Scholar
  39. 39.
    Palmer CD, Mutch BE, Page TH, Horwood NJ, Foxwell BM. Bmx regulates LPS-induced IL-6 and VEGF production via mRNA stability in rheumatoid synovial fibroblasts. Biochem Biophys Res Commun. 2008;370:599–602.CrossRefGoogle Scholar
  40. 40.
    Zhou P, Ma B, Xu S, et al. Knockdown of Burton’s tyrosine kinase confers potent protection against sepsis-induced acute lung injury. Cell Biochem Biophys. 2014;70:1265–1275.CrossRefGoogle Scholar
  41. 41.
    Wang SY, Li FF, Zheng H, et al. Rapid induction and activation of Tec tyrosine kinase in liver regeneration. J Gastroenterol Hepatol. 2006;21:668–673.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Gastroenterology, Qilu HospitalShandong UniversityJinanChina

Personalised recommendations