Inhibition of pulmonary nuclear factor kappa-B decreases the severity of acute Escherichia coli pneumonia but worsens prolonged pneumonia

Critical Care

John G Laffey¹  Daniel O'Toole²  Timothy O'Brien³  Bilal Ansari²  Claire Masterson²  Mairead Hayes²  Gerard F Curley¹  James Devaney² 

[1] Department of Anesthesia, Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, 30 Bond Street, Toronto, ONT, M5B 1W8, Canada;Department of Anaesthesia and Critical Care, School of Medicine, Clinical Sciences Institute, National University of Ireland Galway, University Road, Newcastle, Galway, Ireland;Regenerative Medicine Institute, National University of Ireland Galway, University Road, Newcastle, Galway, Ireland

关键词: gene therapy;    pneumonia;    bacteria;    acute respiratory distress syndrome;    rat;    inhibitory kappa-B alpha;    Acute lung injury;   

Others  :  818158
DOI  :  10.1186/cc12696

 received in 2013-01-17, accepted in 2013-04-27,  发布年份 2013

【 摘 要 】

Introduction

Nuclear factor (NF)-κB is central to the pathogenesis of inflammation in acute lung injury, but also to inflammation resolution and repair. We wished to determine whether overexpression of the NF-κB inhibitor IκBα could modulate the severity of acute and prolonged pneumonia-induced lung injury in a series of prospective randomized animal studies.

Methods

Adult male Sprague-Dawley rats were randomized to undergo intratracheal instillation of (a) 5 × 10⁹ adenoassociated virus (AAV) vectors encoding the IκBα transgene (5 × 10⁹ AAV-IκBα); (b) 1 × 10¹⁰ AAV-IκBα; (c) 5 × 10¹⁰ AAV-IκBα; or (d) vehicle alone. After intratracheal inoculation with Escherichia coli, the severity of the lung injury was measured in one series over a 4-hour period (acute pneumonia), and in a second series after 72 hours (prolonged pneumonia). Additional experiments examined the effects of IκBα and null-gene overexpression on E. coli-induced and sham pneumonia.

Results

In acute pneumonia, IκBα dose-dependently decreased lung injury, improving arterial oxygenation and lung static compliance, reducing alveolar protein leak and histologic injury, and decreasing alveolar IL-1β concentrations. Benefit was maximal at the intermediate (1 × 10¹⁰) IκBα vector dose; however, efficacy was diminished at the higher (5 × 10¹⁰) IκBα vector dose. In contrast, IκBα worsened prolonged pneumonia-induced lung injury, increased lung bacterial load, decreased lung compliance, and delayed resolution of the acute inflammatory response.

Conclusions

Inhibition of pulmonary NF-κB activity reduces early pneumonia-induced injury, but worsens injury and bacterial load during prolonged pneumonia.

【 授权许可】

   
2013 Devaney et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Rubenfeld GD: Epidemiology of acute lung injury. Crit Care Med 2003, 31:S276-284.
• [2]Zilberberg MD, Epstein SK: Acute lung injury in the medical ICU: comorbid conditions, age, etiology, and hospital outcome. Am J Respir Crit Care Med 1998, 157:1159-1164.
• [3]Markowicz P, Wolff M, Djedaini K, Cohen Y, Chastre J, Delclaux C, Merrer J, Herman B, Veber B, Fontaine A, et al.: Multicenter prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome: incidence, prognosis, and risk factors: ARDS Study Group. Am J Respir Crit Care Med 2000, 161:1942-1948.
• [4]TenHoor T, Mannino DM, Moss M: Risk factors for ARDS in the United States: analysis of the 1993 National Mortality Followback Study. Chest 2001, 119:1179-1178.
• [5]Park GY, Christman JW: Nuclear factor kappa B is a promising therapeutic target in inflammatory lung disease. Curr Drug Targets 2006, 7:661-668.
• [6]Ishiyama T, Dharmarajan S, Hayama M, Moriya H, Grapperhaus K, Patterson GA: Inhibition of nuclear factor kappaB by IkappaB superrepressor gene transfer ameliorates ischemia-reperfusion injury after experimental lung transplantation. J Thorac Cardiovasc Surg 2005, 130:194-201.
• [7]Matsuda N, Hattori Y, Takahashi Y, Nishihira J, Jesmin S, Kobayashi M, Gando S: Therapeutic effect of in vivo transfection of transcription factor decoy to NF-kappaB on septic lung in mice. Am J Physiol 2004, 287:L1248-1255.
• [8]Matsuda N, Hattori Y, Jesmin S, Gando S: Nuclear factor-kappaB decoy oligodeoxynucleotides prevent acute lung injury in mice with cecal ligation and puncture-induced sepsis. Mol Pharmacol 2005, 67:1018-1025.
• [9]Rahman A, Fazal F: Blocking NF-kappaB: an inflammatory issue. Proc Am Thorac Soc 2011, 8:497-503.
• [10]Batra S, Balamayooran G, Sahoo MK: Nuclear factor-kappaB: a key regulator in health and disease of lungs. Arch Immunol Ther Exp 2011, 59:335-351.
• [11]Lavon I, Goldberg I, Amit S, Landsman L, Jung S, Tsuberi BZ, Barshack I, Kopolovic J, Galun E, Bujard H, et al.: High susceptibility to bacterial infection, but no liver dysfunction, in mice compromised for hepatocyte NF-kappaB activation. Nat Med 2000, 6:573-577.
• [12]O'Croinin DF, Hopkins NO, Moore MM, Boylan JF, McLoughlin P, Laffey JG: Hypercapnic acidosis does not modulate the severity of bacterial pneumonia-induced lung injury. Crit Care Med 2005, 33:2606-2612.
• [13]Ni Chonghaile M, Higgins BD, Costello JF, Laffey JG: Hypercapnic acidosis attenuates severe acute bacterial pneumonia-induced lung injury by a neutrophil-independent mechanism. Crit Care Med 2008, 36:3135-3144.
• [14]Chonghaile MN, Higgins BD, Costello J, Laffey JG: Hypercapnic acidosis attenuates lung injury induced by established bacterial pneumonia. Anesthesiology 2008, 109:837-848.
• [15]Sen S, Conroy S, Hynes SO, McMahon J, O'Doherty A, Bartlett JS, Akhtar Y, Adegbola T, Connolly CE, Sultan S, et al.: Gene delivery to the vasculature mediated by low-titre adeno-associated virus serotypes 1 and 5. J Gene Med 2008, 10:143-151.
• [16]Hassett P, Curley GF, Contreras M, Masterson C, Higgins BD, O'Brien T, Devaney J, O'Toole D, Laffey JG: Overexpression of pulmonary extracellular superoxide dismutase attenuates endotoxin-induced acute lung injury. Intensive Care Med 2011, 37:1680-1687.
• [17]O'Croinin DF, Nichol AD, Hopkins N, Boylan J, O'Brien S, O'Connor C, Laffey JG, McLoughlin P: Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury. Crit Care Med 2008, 36:2128-2135.
• [18]Laffey JG, Honan D, Hopkins N, Hyvelin JM, Boylan JF, McLoughlin P: Hypercapnic acidosis attenuates endotoxin-induced acute lung injury. Am J Respir Crit Care Med 2004, 169:46-56.
• [19]Contreras M, Ansari B, Curley G, Higgins BD, Hassett P, O'Toole D, Laffey JG: Hypercapnic acidosis attenuates ventilation-induced lung injury by a nuclear factor-kappaB-dependent mechanism. Crit Care Med 2012, 40:2622-2630.
• [20]O'Toole D, Hassett P, Contreras M, Higgins B, McKeown S, McAuley D, O'Brien T, Laffey J: Hypercapnic acidosis attenuates pulmonary epithelial wound repair by an NF-kB dependent mechanism. Thorax 2009, 64:976-982.
• [21]Fein AM, Lippmann M, Holtzman H, Eliraz A, Goldberg SK: The risk factors, incidence, and prognosis of ARDS following septicemia. Chest 1983, 83:40-42.
• [22]Martin MA, Silverman HJ: Gram-negative sepsis and the adult respiratory distress syndrome. Clin Infect Dis 1992, 14:1213-1228.
• [23]Markowicz P, Wolff M, Djedaini K, Cohen Y, Chastre J, Delclaux C, Merrer J, Herman B, Veber B, Fontaine A, et al.: Multicenter prospective study of ventilator-associated pneumonia during acute respiratory distress syndrome: incidence, prognosis, and risk factors: ARDS Study Group. Am J Respir Crit Care Med 2000, 161:1942-1948.
• [24]Freeman BD, Correa R, Karzai W, Natanson C, Patterson M, Banks S, Fitz Y, Danner RL, Wilson L, Eichacker PQ: Controlled trials of rG-CSF and CD11b-directed MAb during hyperoxia and E. coli pneumonia in rats. J Appl Physiol 1996, 80:2066-2076.
• [25]Karzai W, von Specht BU, Parent C, Haberstroh J, Wollersen K, Natanson C, Banks SM, Eichacker PQ: G-CSF during Escherichia coli versus Staphylococcus aureus pneumonia in rats has fundamentally different and opposite effects. Am J Respir Crit Care Med 1999, 159:1377-1382.
• [26]Russo TA, Bartholomew LA, Davidson BA, Helinski JD, Carlino UB, Knight PR, Beers MF, Atochina EN, Notter RH, Holm BA: Total extracellular surfactant is increased but abnormal in a rat model of gram-negative bacterial pneumonia. Am J Physiol Lung Cell Mol Physiol 2002, 283:L655-663.
• [27]Song GW, Robertson B, Curstedt T, Gan XZ, Huang WX: Surfactant treatment in experimental Escherichia coli pneumonia. Acta Anaesthesiol Scand 1996, 40:1154-1160.
• [28]Zeni F, Parent C, Correa R, Natanson C, Freeman B, Fontana J, Quezado M, Danner RL, Fitz Y, Richmond S, et al.: ICAM-1 and CD11b inhibition worsen outcome in rats with E. coli pneumonia. J Appl Physiol 1999, 87:299-307.
• [29]Zhai R, Zhou W, Gong MN, Thompson BT, Su L, Yu C, Kraft P, Christiani DC: Inhibitor kappaB-alpha haplotype GTC is associated with susceptibility to acute respiratory distress syndrome in Caucasians. Crit Care Med 2007, 35:893-898.
• [30]Adamzik M, Frey UH, Rieman K, Sixt S, Beiderlinden M, Siffert W, Peters J: Insertion/deletion polymorphism in the promoter of NFKB1 influences severity but not mortality of acute respiratory distress syndrome. Intensive Care Med 2007, 33:1199-1203.
• [31]McMillan DH, Baglole CJ, Thatcher TH, Maggirwar S, Sime PJ, Phipps RP: Lung-targeted overexpression of the NF-kappaB member RelB inhibits cigarette smoke-induced inflammation. Am J Pathol 2011, 179:125-133.
• [32]Ye X, Ding J, Zhou X, Chen G, Liu SF: Divergent roles of endothelial NF-kappaB in multiple organ injury and bacterial clearance in mouse models of sepsis. J Exp Med 2008, 205:1303-1315.
• [33]Sadikot RT, Zeng H, Joo M, Everhart MB, Sherrill TP, Li B, Cheng DS, Yull FE, Christman JW, Blackwell TS: Targeted immunomodulation of the NF-kappaB pathway in airway epithelium impacts host defense against Pseudomonas aeruginosa. J Immunol 2006, 176:4923-4930.
• [34]Egan LJ, Eckmann L, Greten FR, Chae S, Li ZW, Myhre GM, Robine S, Karin M, Kagnoff MF: IkappaB-kinasebeta-dependent NF-kappaB activation provides radioprotection to the intestinal epithelium. Proc Natl Acad Sci USA 2004, 101:2452-2457.
• [35]Yang G, Abate A, George AG, Weng YH, Dennery PA: Maturational differences in lung NF-kappaB activation and their role in tolerance to hyperoxia. J Clin Invest 2004, 114:669-678.
• [36]Alvira CM, Abate A, Yang G, Dennery PA, Rabinovitch M: Nuclear factor-kappaB activation in neonatal mouse lung protects against lipopolysaccharide-induced inflammation. Am J Respir Crit Care Med 2007, 175:805-815.
• [37]Curley G, Contreras MM, Nichol AD, Higgins BD, Laffey JG: Hypercapnia and acidosis in sepsis: a double-edged sword? Anesthesiology 2010, 112:462-472.
• [38]Laffey JG, O'Croinin D, McLoughlin P, Kavanagh BP: Permissive hypercapnia: role in protective lung ventilatory strategies. Intensive Care Med 2004, 30:347-356.
• [39]Groesdonk HV, Schlottmann S, Richter F, Georgieff M, Senftleben U: Escherichia coli prevents phagocytosis-induced death of macrophages via classical NF-kappaB signaling, a link to T-cell activation. Infect Immun 2006, 74:5989-6000.