The role of Toll-like receptors in non-infectious lung injury

Jiang, Dianhua; Liang, Jiurong; Li, Yu-Hang; Noble, Paul W.

doi:10.1038/sj.cr.7310085

Cited by 134 publications

(122 citation statements)

References 99 publications

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“…27 The noninfectious lung injury was also shown to involve TLR2, TLR4, and fragmented extracellular matrix product hyaluronan as their ligand. 28 Our present study in a clinically relevant "cold" ischemia OLT model extends previous findings from nontransplant local "warm" ischemia settings. Interestingly, intrahepatic disruption of TLR4 signaling was sufficient to prevent liver IRI and did not require adjunctive treatment.…”

Section: Discussionsupporting

confidence: 85%

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Shen

Zhai

et al. 2007

Liver Transpl

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This study analyzes how toll-like receptor 4 (TLR4) signaling in the donor organ affects the ischemia and reperfusion injury (IRI) sequel following liver transplantation. Isogenic orthotopic liver transplantations (OLTs) with rearterialization were performed in groups of wild-type (WT) and TLR4 knockout (KO) mice after donor liver preservation in University of Wisconsin solution at 4°C for 24 hours. Unlike WT OLTs, TLR4-deficient OLTs transplanted to either WT or TLR4 KO recipients suffered significantly less hepatocellular damage, as evidenced by serum alanine aminotransferase levels, and histological Suzuki's grading of liver IRI. Disruption of TLR4 signaling in OLTs decreased local neutrophil sequestration, CD4 ϩ T cell infiltration, interferon (IFN)-␥-inducible protein 10 (CXCL10) and an intercellular adhesion molecule (ICAM-1), as well as tumor necrosis factor (TNF)-␣, interleukin (IL)-1␤, IL-2, and IFN-␥, yet increased IL-4 and IL-10 expression. The well-functioning OLTs from TLR4 KO donors revealed attenuated activity of capase-3, and enhanced heme oygenase-1 (HO-1) expression, along with decreased levels of apoptotic endothelial cells/hepatocytes, as compared with WT OLTs with intact TLR4 signaling. Thus, the functional sentinel TLR4 complex in the donor organ plays a key role in the mechanism of hepatic IRI after OLT. Disruption of TLR4 pathway downregulated the early proinflammatory responses and ameliorated hepatic IRI. These results provide the rationale to locally modify innate TLR4 signaling in the donor organ to more efficiently control the adaptive posttransplantation IRI-dependent responses. Liver Transpl 13:1435-1443, 2007. © 2007 AASLD. Received February 7, 2007 accepted May 19, 2007.The ischemia and reperfusion injury (IRI), an antigenindependent event, is an unavoidable consequence of liver transplantation. The IRI causes up to 10% of early organ failure, and can lead to a higher incidence of both acute and chronic rejection. Indeed, IRI is more frequently observed with the use of marginal donors or following prolonged cold ischemia times. 1-3 Moreover, IRI contributes to the shortage of livers available for transplantation because of the higher susceptibility of marginal organs to the ischemic insult. Thus, minimizing the impact of IRI could significantly increase the number of patients successfully undergoing liver transplantation. The mechanisms of IRI include activation of Kupffer cells with production of reactive oxygen species, upregulation of the inducible nitric oxide synthase, release of proinflammatory cytokines, increased expres-

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Section: Discussionsupporting

confidence: 85%

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Shen

Zhai

et al. 2007

Liver Transpl

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“…29 The function of TLRs is not limited to pathogen control, and TLR2 and TLR4 have been implicated in wound healing in a noninfectious lung injury model. 38 In addition, TLR2 and TLR4 have not only been reported to recognize "stranger signals " from bacteria but also to transduce endogenous "danger signals " like fibronectin, 39 hyaluron acid, 40 and HMGB1, 41 all of which may be found at abundance within large areas of tissue necrosis in the setting of brain abscess. Thus, in our model, TLR2 and TLR4 might be required to limit the size and to resolve the abscess.…”

Section: Discussionmentioning

confidence: 99%

Both TLR2 and TLR4 Are Required for the Effective Immune Response in Staphylococcus aureus-Induced Experimental Murine Brain Abscess

Stenzel

Soltek

Sánchez‐Ruiz

et al. 2008

The American Journal of Pathology

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Toll-like receptors (TLRs) play central roles in the innate reaction to bacterial products and transmit specific immune responses against these pathogens. TLRs are expressed on numerous cell types, including innate immune cells, and on astrocytes, neurons, and microglial cells of the central nervous system (CNS). Lipoproteins and lipopolysaccharides are specifically recognized by TLR2 and TLR4, respectively. We examined the in vivo role of TLR2 and TLR4 in Staphylococcus aureus-induced brain abscess. Phenotypically, 87% of TLR2 ؊/؊ mice and 43% of TLR4 ؊/؊ mice died whereas all wild-type (WT) mice recovered. Clearance of bacteria from the CNS was significantly delayed in TLR2 ؊/؊ mice compared with TLR4 ؊/؊ and WT animals. Recruitment of granulocytes and macrophages to the CNS, as well as microglial activation and expansion, was up-regulated in TLR2 ؊/؊ mice. Although inflammation persisted especially in the CNS of TLR2 ؊/؊ mice, but also of TLR4 ؊/؊ mice, WT mice terminated the infection more effectively. Collectively, these data show that the immune response to experimental S. aureus-induced brain abscess depends crucially on the recognition of S. aureus by TLR2 but that TLR4 is also required for an optimal intracerebral immune response in this disorder.

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“…Of considerable interest, tlr9 -/-mice displayed a strongly enhanced lung consolidation during MRSA pneumonia, suggesting that TLR9 signaling contributes to the resolution of lung inflammation. In this respect, it is interesting to note that TLR signaling has been reported to contribute to the resolution of lung inflammation in noninfectious conditions (46,47).…”

Section: Tlr9 Deficiency Is Associated With Strongly Increased Lung Cmentioning

confidence: 99%

Toll-Like Receptor 9 Enhances Bacterial Clearance and Limits Lung Consolidation in Murine Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

Meer

Achouiti

Ende

et al. 2016

Mol Med

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The role of Toll-like receptors in non-infectious lung injury

Cited by 134 publications

References 99 publications

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Absence of toll-like receptor 4 (TLR4) signaling in the donor organ reduces ischemia and reperfusion injury in a murine liver transplantation model

Both TLR2 and TLR4 Are Required for the Effective Immune Response in Staphylococcus aureus-Induced Experimental Murine Brain Abscess

Toll-Like Receptor 9 Enhances Bacterial Clearance and Limits Lung Consolidation in Murine Pneumonia Caused by Methicillin-Resistant Staphylococcus aureus

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