Hostname: page-component-cd9895bd7-dk4vv Total loading time: 0 Render date: 2024-12-26T06:15:54.377Z Has data issue: false hasContentIssue false
  • English
  • Français

Role of Toll-like receptor 4 for the pathogenesis of acute lung injury in Gram-negative sepsis

Published online by Cambridge University Press:  12 July 2006

G. Baumgarten ,
P. Knuefermann ,
H. Wrigge ,
C. Putensen ,
H. Stapel ,
K. Fink ,
R. Meyer ,
A. Hoeft  and
C. Grohé
G. Baumgarten
Affiliation:
Universitätsklinikum Bonn, Department of Anesthesiology and Intensive Care Medicine, Bonn, Germany
P. Knuefermann
Affiliation:
Universitätsklinikum Bonn, Department of Anesthesiology and Intensive Care Medicine, Bonn, Germany
H. Wrigge
Affiliation:
Universitätsklinikum Bonn, Department of Anesthesiology and Intensive Care Medicine, Bonn, Germany
C. Putensen
Affiliation:
Universitätsklinikum Bonn, Department of Anesthesiology and Intensive Care Medicine, Bonn, Germany
H. Stapel
Affiliation:
Universitätsklinikum Bonn, Department of Anesthesiology and Intensive Care Medicine, Bonn, Germany
K. Fink
Affiliation:
Universitätsklinikum Bonn, Department of Pharmacology and Toxicology, Bonn, Germany
R. Meyer
Affiliation:
Universitätsklinikum Bonn, Institute of Physiology II, Bonn, Germany
A. Hoeft
Affiliation:
Universitätsklinikum Bonn, Department of Anesthesiology and Intensive Care Medicine, Bonn, Germany
C. Grohé
Affiliation:
Universitätsklinikum Bonn, Medizinische Univ.-Poliklinik, Bonn, Germany
Get access

Abstract

Summary

Background and objective: Proinflammatory cytokines as well as nitric oxide (NO) play a major role in mediating the response to lipopolysaccharide (LPS). The present study tested the hypothesis that LPS induces proinflammatory cytokines in the lung via the Toll-like receptor 4 (TLR4)/CD14 signalling cascade. Methods: Control mice and TLR4-deficient (TLR4-D) mice were used to test TLR4-mediated effects of LPS. Both strains received either Escherichia coli LPS (20 mg kg−1 intraperitoneal) or saline and their lungs were collected at different time points. Pulmonary nuclear factor κB (NFκB) activation was investigated with electromobility shift assay. mRNA expression of inflammatory mediators and their corresponding receptors were detected with Ribonuclease Protection Assay. Protein expression was detected by ELISA and western blotting. Inducible NO synthase (iNOS) expression was monitored by RT-PCR and iNOS activity by conversion of l-arginine to citrulline. Immune cells were sampled by bronchoalveolar lavage (BAL) and classified. Results: LPS application induced CD14-, but not TLR4 protein expression in control mice. Activation of pulmonary NFκB was observed within 60 min in control, but not in TLR4-D mice. Six hours of LPS administration induced a significant increase in pulmonary tumour necrosis factor α-, interleukin-1β- and interleukin-6 mRNA and protein expression in control mice compared to TLR4-D mice. Furthermore, LPS induced a significantly higher increase of the iNOS expression and catalytic activity in control mice than in TLR4-D mice. BAL revealed an increase in total cell count in all LPS treated mice. Conclusion: Our findings suggest that TLR4 plays a key role for regulating the expression of relevant cytokines within the lung during endotoxic shock.

Keywords

RESPIRATORY DISTRESS SYNDROME ADULTTOLL-LIKE RECEPTORSINFLAMMATIONCYTOKINESSEPSIS SYNDROMEMICE
Type
Original Article
Information
European Journal of Anaesthesiology , Volume 23 , Issue 12 , December 2006 , pp. 1041 - 1048
Copyright
2006 European Society of Anaesthesiology

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Wheeler AP, Bernard GR. Treating patients with severe sepsis. New Engl J Med 1999; 340: 207–215.Google Scholar
Chow CW, Herrera Abreu MT, Suzuki T, Downey GP. Oxidative stress and acute lung injury. Am J Respir Cell Mol Biol 2003; 29: 427–431.Google Scholar
Vincent JL, Akca S, De Mendonca A et al. The epidemiology of acute respiratory failure in critically ill patients. Chest 2002; 121: 1602–1609.Google Scholar
Stuber F, Wrigge H, Schroeder Set al. Kinetic and reversibility of mechanical ventilation-associated pulmonary and systemic inflammatory response in patients with acute lung injury. Intens Care Med 2002; 28: 834–841.Google Scholar
Wrigge H, Zinserling J, Stuber Fet al. Effects of mechanical ventilation on release of cytokines into systemic circulation in patients with normal pulmonary function. Anesthesiology 2000; 93: 1413–1417.Google Scholar
Qu J, Zhang J, Pan Jet al. Endotoxin talerance inhibits lipopolysaccharide-initiated acute pulmonary inflammation and lung injury in rats by the mechanism of nuclear factor-kappaB. Scand J Immunol 2003; 58: 613–619.Google Scholar
dos Santos CC, Han B, Andrade CFet al. DNA microarray analysis of gene expression in alveolar epithelial cells in response to TNFalpha, LPS, and cyclic stretch. Physiol Genomics 2004; 19: 331–342.Google Scholar
Baumgarten G, Knuefermann P, Nozaki N, Sivasubramanian N, Mann DL, Vallejo JG. In vivo expression of proinflammatory mediators in the adult heart after endotoxin administration: the role of toll-like receptor-4. J Infect Dis 2001; 183: 1617–1624.Google Scholar
Nemoto S, Vallejo JG, Knuefermann Pet al. Escherichia coli LPS-induced LV dysfunction: role of toll-like receptor-4 in the adult heart. Am J Physiol Heart Circ Physiol 2002; 282: H2316–H2323.Google Scholar
Knuefermann P, Nemoto S, Misra Aet al. CD14-deficient mice are protected against lipopolysaccharide-induced cardiac inflammation and left ventricular dysfunction. Circulation 2002; 106: 2608–2615.Google Scholar
Baumgarten G, Knuefermann P, Schumacher Get al. Toll-Like receptor 4, NO and myocardial depression in endotoxemia. Shock 2006; 25 (1): 43–49.Google Scholar
Kopp EB, Medzhitov R. The Toll-receptor family and control of innate immunity. Curr Opin Immunol 1999; 11: 13–18.Google Scholar
Beutler B. Innate immunity: an overview. Mol Immunol 2004; 40: 845–859.Google Scholar
Poltorak A, He X, Smirnova Iet al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 1998; 282: 2085–2088.Google Scholar
Yoshimura A, Lien E, Ingalls RR, Tuomanen E, Dziarski R, Golenbock D. Cutting edge: recognition of Gram-positive bacterial cell wall components by the innate immune system occurs via Toll-like receptor 2. J Immunol 1999; 163: 1–5.Google Scholar
Schuster JM, Nelson PS. Toll receptors: an expanding role in our understanding of human disease. J Leukoc Biol 2000; 67: 767–773.Google Scholar
Frantz S, Kobzik L, Kim YDet al. Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium. J Clin Invest 1999; 104: 271–280.Google Scholar
Poltorak A, Smirnova I, He Xet al. Genetic and physical mapping of the Lps locus: identification of the toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol Dis 1998; 24: 340–355.Google Scholar
Perera PY, Mayadas TN, Takeuchi Oet al. CD11b/CD18 acts in concert with CD14 and Toll-like receptor (TLR) 4 to elicit full lipopolysaccharide and taxol-inducible gene expression. J Immunol 2001; 166: 574–581.Google Scholar
Knuefermann P, Chen P, Misra A, Shi SP, Abdellatif M, Sivasubramanian N. Myotrophin/V-1, a protein up-regulated in the failing human heart and in postnatal cerebellum, converts NFkappa B p50–p65 heterodimers to p50–p50 and p65–p65 homodimers. J Biol Chem 2002; 277: 23888–23897.Google Scholar
Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987; 162: 156–159.Google Scholar
Bredt DS, Hwang PM, Snyder SH. Localization of nitric oxide synthase indicating a neural role for nitric oxide. Nature 1990; 347: 768–770.Google Scholar
Fonseca-Aten M, Rios AM, Mejias Aet al. Mycoplasma pneumoniae induces host-dependent pulmonary inflammation and airway obstruction in mice. Am J Respir Cell Mol Biol 2005; 32: 201–210.Google Scholar
Fan J, Kapus A, Marsden PAet al. Regulation of Toll-like receptor 4 expression in the lung following hemorrhagic shock and lipopolysaccharide. J Immunol 2002; 168: 5252–5259.Google Scholar
Guillot L, Medjane S, Le Barillec Ket al. Response of human pulmonary epithelial cells to LPS involves toll-like receptor 4 (TLR4)-dependent signaling pathways: evidence for an intracellular compartmentalization of TLR4. J Biol Chem 2004; 279 (4): 2712–2718.Google Scholar
Oshikawa K, Sugiyama Y. Gene expression of Toll-like receptors and associated molecules induced by inflammatory stimuli in the primary alveolar macrophage. Biochem Biophys Res Commun 2003; 305: 649–655.Google Scholar
Fearns C, Kravchenko VV, Ulevitch RJ, Loskutoff DJ. Murine CD14 gene expression in vivo : extramyeloid synthesis and regulation by lipopolysaccharide. J Exp Med 1995; 181: 857–866.Google Scholar
Poynter ME, Irvin CG, Janssen-Heininger YM. A prominent role for airway epithelial NF-kappa B activation in lipopolysaccharide-induced airway inflammation. J Immunol 2003; 170: 6257–6265.Google Scholar
Cui X, Rouhani FN, Hawari F, Levine SJ. Shedding of the type II IL-1 decoy receptor requires a multifunctional aminopeptidase, aminopeptidase regulator of TNF receptor type 1 shedding. J Immunol 2003; 171: 6814–6819.Google Scholar
Jablonska E, Jabionski J, Holownia Aet al. TNFRs and IL-6R transmembrane receptors expression and release of their soluble forms by neutrophils and mononuclear cells from cancer patients. Rocz Akad Med Bialymst 2001; 46: 113–125.Google Scholar
Lynn M, Rossignol DP, Wheeler JLet al. Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia. J Infect Dis 2003; 187: 631–639.Google Scholar