Knockout of PKC θ gene attenuates oleic acid-induced acute lung injury via reduction of inflammation and oxidative stress

Document Type : Original Article

Authors

1 Department of Pathophysiology, Wannan Medical College, Wuhu, China

2 Experimental Center for Function Subjects, Wannan Medical College, Wuhu, China

Abstract

Objective(s): Acute respiratory distress syndrome resulting from acute lung injury has become a momentous clinical concern because of high morbidity and mortality in discharged patients with pulmonary and nonpulmonary diseases. This study aimed to explore the effect of protein kinase C (PKC) θ gene knockout on acute lung injury.
Materials and Methods: Wt and PKC θ gene knockout mice were intravenously injected with oleic acid to induce acute lung injury. Pulmonary capillary permeability was assessed via measuring lung wet/dry weight ratio and level of protein in bronchoalveolar lavage fluid (BALF). Histological changes were used to examine acute lung injury. Malondialdehyde (MDA) level, superoxide dismutase (SOD) activity in serum, together with inflammatory cytokines including interleukin (IL)-6 and tumor necrosis factor-alpha (TNF-α), were determined. Furthermore, the expressions of heme oxygenase (HO)-1, nuclear factor kappa B (NF κB), and inhibitor of NF-κB alpha (IκB α) were detected in the lungs.
Results: PKC θ gene knockout decreased lung wet/dry weight ratio, reduced levels of MDA, IL-6, and TNF-α in serum together with level of protein in BALF. Furthermore, PKC θ gene knockout increased the activities of SOD.  Knockout of PKC θ was also observed to increase expression of HO-1 and reduce levels of p-NF κB and p-IKB α in the lungs.
Conclusion: These results suggest that PKC θ gene knockout attenuates oleic acid-induced acute lung injury via improving oxidative stress and inflammation.

Keywords


1. Dagvadorj J, Shimada K, Chen S, Jones HD, Tumurkhuu G, Zhang W, et al. Lipopolysaccharide induces alveolar macrophage necrosis via CD14 and the P2X7 receptor leading to interleukin-1alpha release. Immunity 2015; 42:640-653.
2. Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012; 122:2731-2740.
3. Davidson TA, Caldwell ES, Curtis JR, Hudson LD, Steinberg KP. Reduced quality of life in survivors of acute respiratory distress syndrome compared with critically ill control patients. JAMA 1999; 281:354-360.
4. Maulik N, Das DK. Redox signaling in vascular angiogenesis. Free Radic Biol Med 2002; 33:1047-1060.
5. Mukhopadhyay S, Hoidal JR, Mukherjee TK. Role of TNFalpha in pulmonary pathophysiology. Respir Res 2006; 7:125.
6. Li HX, Zhang JC, Zhao YL, Hao HJ. [Effects of interleukin-10 on expression of inflammatory mediators and anti-inflammatory mediators during acute lung injury in rats]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue 2005; 17:338-341.
7. Moriuchi H, Zaha M, Fukumoto T, Yuizono T. Activation of polymorphonuclear leukocytes in oleic acid-induced lung injury. Intensive Care Med 1998; 24:709-715.
8. Krause KH, Bedard K. NOX enzymes in immuno-inflammatory pathologies. Semin Immunopathol 2008; 30:193-194.
9. Porter JC, Hall A. Epithelial ICAM-1 and ICAM-2 regulate the egression of human T cells across the bronchial epithelium. FASEB J 2009; 23:492-502.
10. Tyml K, Li F, Wilson JX. Septic impairment of capillary blood flow requires nicotinamide adenine dinucleotide phosphate oxidase but not nitric oxide synthase and is rapidly reversed by ascorbate through an endothelial nitric oxide synthase-dependent mechanism. Crit Care Med 2008; 36:2355-2362.
11. Cosentino-Gomes D, Rocco-Machado N, Meyer-Fernandes JR. Cell signaling through protein kinase C oxidation and activation. Int J Mol Sci 2012; 13:10697-10721.
12. Gao X, Schottker B. Reduction-oxidation pathways involved in cancer development: A systematic review of literature reviews. Oncotarget 2017; 8:51888-51906.
13. Steinberg SF. Mechanisms for redox-regulation of protein kinase C. Front Pharmacol 2015; 6:128-146.
14. Thallas-Bonke V, Jha JC, Gray SP, Barit D, Haller H, Schmidt HH, et al. Nox-4 deletion reduces oxidative stress and injury by PKC-alpha-associated mechanisms in diabetic nephropathy. Physiol Rep 2014; 2-18.
15. Marsland BJ, Soos TJ, Spath G, Littman DR, Kopf M. Protein kinase C theta is critical for the development of in vivo T helper (Th)2 cell but not Th1 cell responses. J Exp Med 2004; 200:181-189.
16. Baier G, Telford D, Giampa L, Coggeshall KM, Baier-Bitterlich G, Isakov N, et al. Molecular cloning and characterization of PKC theta, a novel member of the protein kinase C (PKC) gene family expressed predominantly in hematopoietic cells. J Biol Chem 1993; 268:4997-5004.
17. Baier G. The PKC gene module: molecular biosystematics to resolve its T cell functions. Immunol Rev 2003; 192:64-79.
18. Peck B, Huot J, Renzi T, Arthur S, Turner MJ, Marino JS. Mice lacking PKC-theta in skeletal muscle have reduced intramyocellular lipid accumulation and increased insulin responsiveness in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 2018; 314:R468-R477.
19. Healy AM, Izmailova E, Fitzgerald M, Walker R, Hattersley M, Silva M, et al. PKC-theta-deficient mice are protected from Th1-dependent antigen-induced arthritis. J Immunol 2006; 177:1886-1893.
20. Salek-Ardakani S, So T, Halteman BS, Altman A, Croft M. Differential regulation of Th2 and Th1 lung inflammatory responses by protein kinase C theta. J Immunol 2004; 173:6440-6447.
21. Schuster DP. ARDS: clinical lessons from the oleic acid model of acute lung injury. Am J Respir Crit Care Med 1994; 149:245-260.
22. Matute-Bello G, Frevert CW, Martin TR. Animal models of acute lung injury. Am J Physiol Lung Cell Mol Physiol 2008; 295:L379-399.
23. Lang JD, McArdle PJ, O’Reilly PJ, Matalon S. Oxidant-anti-oxidant balance in acute lung injury. Chest 2002; 122:314S-320S.
24. Li JW, Wu X. Mesenchymal stem cells ameliorate LPS-induced acute lung injury through KGF promoting alveolar fluid clearance of alveolar type II cells. Eur Rev Med Pharmacol Sci 2015; 19:2368-2378.
25. Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: The Berlin Definition. JAMA 2012; 307:2526-2533.
26. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818-824.
27. Matthay MA, Zemans RL. The acute respiratory distress syndrome: pathogenesis and treatment. Annu Rev Pathol 2011; 6:147-163.
28. Ware LB, Matthay MA. Clinical practice. Acute pulmonary edema. N Engl J Med 2005; 353:2788-2796.
29. Ulrich K, Stern M, Goddard ME, Williams J, Zhu J, Dewar A, et al. Keratinocyte growth factor therapy in murine oleic acid-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 2005; 288:L1179-1192.
30. Matthay MA, Calfee CS. Therapeutic value of a lung protective ventilation strategy in acute lung injury. Chest 2005; 128:3089-3091.
31. Bertram A, Ley K. Protein kinase C isoforms in neutrophil adhesion and activation. Arch Immunol Ther Exp (Warsz) 2011; 59:79-87.
32. Xu J, Yang G, Li T, Ming J, Liu L. Involvement of Cpi-17 and zipper-interacting protein kinase in the regulation of protein kinase C-alpha, protein kinase C-epsilon on vascular calcium sensitivity after hemorrhagic shock. Shock 2010; 33:49-55.
33. Shi C, Zhao X, Wang X, Zhao L, Andersson R. Potential effects of PKC or protease inhibitors on acute pancreatitis-induced tissue injury in rats. Vascul Pharmacol 2007; 46:406-411.
34. Kilpatrick LE, Standage SW, Li H, Raj NR, Korchak HM, Wolfson MR, et al. Protection against sepsis-induced lung injury by selective inhibition of protein kinase C-delta (delta-PKC). J Leukoc Biol 2011; 89:3-10.
35. Bertram A, Zhang H, von Vietinghoff S, de Pablo C, Haller H, Shushakova N, et al. Protein kinase C-theta is required for murine neutrophil recruitment and adhesion strengthening under flow. J Immunol 2012; 188:4043-4051.
36. Chichger H, Grinnell KL, Casserly B, Chung CS, Braza J, Lomas-Neira J, et al. Genetic disruption of protein kinase Cdelta reduces endotoxin-induced lung injury. Am J Physiol Lung Cell Mol Physiol 2012; 303:L880-888.
37. Arendt CW, Albrecht B, Soos TJ, Littman DR. Protein kinase C-theta;: Aignaling from the center of the T-cell synapse. Curr Opin Immunol 2002; 14:323-330.
38. Hall KJ, Harper MT, Gilio K, Cosemans JM, Heemskerk JW, Poole AW. Genetic analysis of the role of protein kinase Ctheta in platelet function and thrombus formation. PLoS One 2008; 3:e3277.
39. Villalba M, Altman A. Protein kinase C-theta (PKCtheta), a potential drug target for therapeutic intervention with human T cell leukemias. Curr Cancer Drug Targets 2002; 2:125-137.
40. Kim YS, Kim JS, Kwon JS, Jeong MH, Cho JG, Park JC, et al. BAY 11-7082, a nuclear factor-kappaB inhibitor, reduces inflammation and apoptosis in a rat cardiac ischemia-reperfusion injury model. Int Heart J 2010; 51:348-353.
41. Fang X, Wang R, Ma J, Ding Y, Shang W, Sun Z. Ameliorated ConA-induced hepatitis in the absence of PKC-theta. PLoS One 2012; 7:e31174.
42. Opitz B, van Laak V, Eitel J, Suttorp N. Innate immune recognition in infectious and noninfectious diseases of the lung. Am J Respir Crit Care Med 2010; 181:1294-1309.
43. Goodman RB, Pugin J, Lee JS, Matthay MA. Cytokine-mediated inflammation in acute lung injury. Cytokine Growth Factor Rev 2003; 14:523-535.
44. Goodman RB, Strieter RM, Martin DP, Steinberg KP, Milberg JA, Maunder RJ, et al. Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome. Am J Respir Crit Care Med 1996; 154:602-611.
45. Steinberg KP, Milberg JA, Martin TR, Maunder RJ, Cockrill BA, Hudson LD. Evolution of bronchoalveolar cell populations in the adult respiratory distress syndrome. Am J Respir Crit Care Med 1994; 150:113-122.
46. Welbourn CR, Goldman G, Paterson IS, Valeri CR, Shepro D, Hechtman HB. Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil. Br J Surg 1991; 78:651-655.
47. Lorne E, Zmijewski JW, Zhao X, Liu G, Tsuruta Y, Park YJ, et al. Role of extracellular superoxide in neutrophil activation: interactions between xanthine oxidase and TLR4 induce proinflammatory cytokine production. Am J Physiol Cell Physiol 2008; 294:C985-993.
48. Wu F, Schuster DP, Tyml K, Wilson JX. Ascorbate inhibits NADPH oxidase subunit p47phox expression in microvascular endothelial cells. Free Radic Biol Med 2007; 42:124-131.
49. Nakamura T, Nakamura H, Hoshino T, Ueda S, Wada H, Yodoi J. Redox regulation of lung inflammation by thioredoxin. Antioxid Redox Signal 2005; 7:60-71.
50. Liu S, Feng G, Wang GL, Liu GJ. p38MAPK inhibition attenuates LPS-induced acute lung injury involvement of NF-kappaB pathway. Eur J Pharmacol 2008; 584:159-165.
51. Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med 2000; 342:1334-1349.
52. Ryter SW, Kim HP, Nakahira K, Zuckerbraun BS, Morse D, Choi AM. Protective functions of heme oxygenase-1 and carbon monoxide in the respiratory system. Antioxid Redox Signal 2007; 9:2157-2173.
53. Chakraborty P, Saraswat G, Kabir SN. Alpha-dihydroxychalcone-glycoside (alpha-DHC) isolated from the heartwood of Pterocarpus marsupium inhibits LPS induced MAPK activation and up regulates HO-1 expression in murine RAW 264.7 macrophage. Toxicol Appl Pharmacol 2014; 277:95-107.
54. Bellezza I, Tucci A, Galli F, Grottelli S, Mierla AL, Pilolli F, et al. Inhibition of NF-kappaB nuclear translocation via HO-1 activation underlies alpha-tocopheryl succinate toxicity. J Nutr Biochem 2012; 23:1583-1591.