TNF-alpha decreases infection-induced lung injury in burn through negative regulation of TLR4/iNOS.

Abstract

BACKGROUND:

Sepsis is an infectious process-induced generalized inflammatory response that mediates the excessive production of cytokines. However, anti-tumor necrosis factor (TNF)-α therapy has failed in decreasing mortality of sepsis patients due to undefined mechanisms. This study was designed to investigate whether absence of TNF receptor enhanced lung damage and mortality through toll-like receptors (TLRs) and inducible nitric oxide synthase (iNOS).

MATERIALS AND METHODS:

We injected Pseudomonas aeruginosa or lipopolysaccharide in the backs of wild-type, Tnfrsf1a(-/-) (deficient of TNF-α receptor 1), and TLR4(-/-) mice at 8 h after 30% total body surface area burn. The animals were sacrificed at 16 h after burn and lung tissues were harvested and examined for determining pulmonary microvascular dysfunction and interleukin (IL)-1β, iNOS, and TLR4 expression. The blood of animals was harvested for bacterial count assay. The effect of S-methylisothiourea, an iNOS inhibitor, on P aeruginosa infection with thermal injury pretreatment-induced lung damage was also examined.

RESULTS:

P aeruginosa or lipopolysaccharide injection with thermal injury pretreatment enhanced TLR4, iNOS, and IL-1β expression and pulmonary microvascular dysfunction in Tnfrsf1a(-/-) mice compared with wild-type mice. P aeruginosa infection with thermal injury pretreatment did not induce IL-1β or iNOS expression and mortality in TLR4(-/-) mice. S-methylisothiourea treatment significantly decreased P aeruginosa infection with thermal injury pretreatment-induced lung injury, blood bacterial counts, pulmonary IL-1β expression, and mortality in Tnfrsf1a(-/-) mice.

CONCLUSIONS:

Given that absence of the TNF-α receptor 1 is associated with increased lung permeability, we conclude that TNF-α decreases P aeruginosa infection-induced lung damage in burn mice through negative regulation of TLR4 as well as iNOS expression, and iNOS inhibitor might be useful in reversing anti-TNF-α therapy-induced lung injury in burn.

• Authors: Tzyy-Bin Tsay, Ming-Chieh Yang, Pei-Hsuan Chen, Cheng-Ta Lin, Ching-Mei Hsu, Lee-Wei Chen
• Journal: The Journal of surgical research (J Surg Res) Vol. 179 Issue 1 Pg. 106-14 (Jan 2013) ISSN: 1095-8673 [Electronic] United States
• PMID: 22995661 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Inc. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Interleukin-1beta
• Lipopolysaccharides
• Receptors, Tumor Necrosis Factor, Type I
• Tlr4 protein, mouse
• Tnfrsf1a protein, mouse
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• Isothiuronium
• Nitric Oxide Synthase Type II
• S-methylisothiopseudouronium

Topics

• Animals
• Burns (complications, epidemiology)
• Comorbidity
• Enzyme Inhibitors (therapeutic use)
• Interleukin-1beta (metabolism)
• Isothiuronium (analogs & derivatives, therapeutic use)
• Lipopolysaccharides (adverse effects)
• Lung Injury (drug therapy, etiology, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Models, Animal
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Pseudomonas Infections (complications, epidemiology)
• Pseudomonas aeruginosa
• Receptors, Tumor Necrosis Factor, Type I (deficiency, genetics, metabolism)
• Toll-Like Receptor 4 (deficiency, genetics, metabolism)
• Treatment Outcome
• Tumor Necrosis Factor-alpha (therapeutic use)