http://dx.doi.org/10.18081/2333-5106/015-06/333-344
Mariana B. Friedman, Halley A. Schmid, Astor S. Josef, Mark Longton
Abstract
The role of endotoxin in making the lung susceptible to injury and in generating adverse health effects in sensitive populations has profound public health implications. Intriguing and exciting findings reported here demonstrate the functional effects during mild lung inflammation in the airways and correspond to prior findings in humans. Currently available chemotherapeutics do not show localization in blood versus airway compartments of the lung, and new therapies could be developed for these significant public health concerns. These direct findings are significant and will markedly inform the field. Many human lung diseases are associated with systemic and pulmonary inflammation. Here, endotoxin reduces the alveolar clot, increases effective lung clearance, is associated with sufficient hepatic fibrinogen production to normalize plasma fibrinogen levels, and does not perceptibly impair lung function or structure. This is an initial study presenting a detailed analysis of the differential transcriptional changes of a known injury-related signaling pathway – the endotoxin/Toll-Like Receptor 4 (TLR4) transcriptional signature. TLR4 activates ICAM-1; this activated protein was detected both in transduced cells and in the BAL cell pellet of acute cases and controls. A KO of the innate adaptor (TRIF)(TLR-3) blunts transcriptional changes and prevents activation of a transcription site, p65. Inconclusion, signaling pathways activated by Toll-like Receptors have emerged as important regulatory genes in host defense and inflammation. TLR3 is involved in the recognition of viral pathogens. The short extracellular LRR domain and the distinct signaling pathways chosen by TLR3 account for its special role. The Eritoran molecule is related to a reduced level of the local inflammatory reaction to endotoxin in the lung in THP-1-derived MPs in vitro and ex vivo. We conclude that the endotoxin/TLR3 signal transduction pathway may be considered as a potential path for research and therapy in lung injury. Whether this way exists in the body needs to be further studied.
Keywords: TLR3; AKT phosphorylation; proinflammatory cytokine; Lung injury
References
1. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124:783-801. [PubMed]
2. Park JS, Svetkauskaite D, He Q, et al. Involvement of toll‐like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 2004; 279:7370-7377. [PubMed]
3. Kariko K, Ni H, Capodici J, Lamphier M, Weissman D. mRNA is an endogenous ligand for toll‐like receptor 3. J Biol Chem 2004; 279:12542-12550. [PubMed]
4. Cavassani KA, Ishii M, Wen H, et al. TLR3 is an endogenous sensor of tissue necrosis during acute inflammatory events. J Exp Med. 2008; 205:2609-2621. [PubMed]
5. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double‐stranded RNA and activation of NF‐kappaB by toll‐like receptor 3. Nature 2001; 413:732-738. [PubMed]
6. Pinsky, MR. Dysregulation of the immune response in severe sepsis. Am. J. Med Sci 2004;328:220–229. [PubMed]
7. Marshak-Rothstein A. Toll-like receptors in systemic autoimmune disease. Nat. Rev. Immunol 2006; 6:823–835. [PubMed]
8. Doughty LA, Carlton S, Galen B, Cooma-Ramberan I, Chung CS, Ayala A. Activation of common antiviral pathways can potentiate inflammatory responses to septic shock. Shock 2006; 26:187–194. [PubMed]
9. MacDonald KL, Osterholm MT, Hedberg CW, et al. Toxic shock syndrome: a newly recognized complication of influenza and influenza-like illness. JAMA 1987; 257:1053–1058. [PubMed]
10. Zhang WJ, Sarawar S, Nguyen P, et al. Lethal synergism between influenza infection and staphylococcal enterotoxin B in mice. J Immunol 1996;157:5049– 5060.
11. Fejer G, Szalay K, Gyory I, et al. Adenovirus infection dramatically augments lipopolysaccharide-induced TNF production and sensitizes to lethal shock. J Immunol 2005;175:1498 – 1506. [PubMed]
12. Fink MP. Laboratory models of sepsis and septic shock. J Surg Res 1990;49:186 – 196. [PubMed]
13. Latifi SQ, O’Riordan MA, Levine AD. Interleukin-10 controls the onset of irreversible septic shock. Infect Immun 2002;70:4441 – 4446. [PubMed]
14. Yamamoto M, Sato S, Hemmi H, et al. Role of adaptor TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 2003;301:640 – 643. [PubMed]
15. Biron CA. Interferons α and β as immune regulators—a new look. Immunity 2001;14:661 – 664. [PubMed]
16. Jiang Z, Mak TW, Sen G, Li X. Toll-like receptor 3-mediated activation of NFκB and IRF3 diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-β. Proc Natl Acad Sci USA 2004;101:3533 – 3538. [PubMed]
17. Fitzgerald KA, McWhirter SM, Faia KL, et al. IKKα and TBK I are essential components of the IRF3 signaling pathway. Nature 2003;4:491 – 496. [PubMed]
18. WA Everett, NG Yousif, L Ao, JC Cleveland, X Fullerton David A, Meng. Ghrelin reduces myocardial injury following global ischemia and reperfusion via suppression of myocardial inflammatory response. American Journal of BioMedicine 2013;1(1):38-48. [Abstract/Full-Text]
19. Sharma S, tenOever BR, Grandvaux N, Zhou GP, Lin R, Hiscott J. Triggering the interferon antiviral response through an IKK-related pathway. Science 2003;300:1148 – 1151. [PubMed]
20. Borchers MT, Wesselkamper SC, Curull V, et al. Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease. J Clin Invest 2009;119: 636-649. [PubMed]
21. Orr MT, Lanier LL. Natural killer cell education and tolerance. Cell 2010; 142:847-856. [PubMed]
22. Yousif NG, Ao L, Fullerton DA, Meng X. Myocardial tissue TLR4-mediated mcp-1 production contributes to the mechanisms of myocardial injury following cold ischemia and reperfusion. Shock 2011; 35, 65-65.
