Inhibition of Toll-like Receptor 4 With Eritoran Attenuates Myocardial Ischemia-Reperfusion Injury

Shimamoto, Akira; Chong, Albert J.; Yada, Masaki; Shomura, Shin; Takayama, Hiroo; Fleisig, Ani J.; Agnew, Matthew L.; Hampton, Craig R.; Rothnie, Christine L.; Spring, Denise J.; Pohlman, Timothy H.; Shimpo, Hideto; Verrier, Edward D.

doi:10.1161/circulationaha.105.000901

Cited by 238 publications

(187 citation statements)

References 24 publications

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“…However, there was no statistically significant difference among the patients groups. Finally, the minor allele frequencies of both TLR4 variants are rather low as reported previously (16,23,24). Consequently, the frequency of the rs4986790 and rs47986791 haplotype is even lower.…”

Section: Wild Typesupporting

confidence: 61%

“…Loss of TLR4 in knock-out mouse models showed the protective effects in several types of heart failure to include myocardial ischemia, pressure overload, viral myocarditis, and toxic cardiomyopathy (11)(12)(13)(14)(15). Moreover, pharmacological inhibition of TLR4 in mouse models of myocardial ischemia exerts beneficial therapeutic effects (16). In patients with coronary artery disease, the peripheral contents of TLR4-positive monocytes were significantly increased during acute myocardial ischemia (17).…”

Section: Dilated Cardiomyopathy (Dcm)mentioning

confidence: 99%

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Variants of Toll-like Receptor 4 Predict Cardiac Recovery in Patients with Dilated Cardiomyopathy

Riad

Schwabedissen

Weitmann

et al. 2012

Journal of Biological Chemistry

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Background:The impact of polymorphisms of TLR4 on left ventricular performance in DCM patients is unknown. Results: Patients carrying TLR4 variants had reduced improvement of left ventricular function and dilation and no increase in NT-pro-BNP level at follow up when compared with wild type genes. Conclusion: TLR4 variants predict cardiac recovery in DCM.Significance: This is the first study to investigate the impact of an innate immune receptor on cardiac recovery in human DCM.

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Section: Wild Typesupporting

confidence: 61%

Section: Dilated Cardiomyopathy (Dcm)mentioning

confidence: 99%

Variants of Toll-like Receptor 4 Predict Cardiac Recovery in Patients with Dilated Cardiomyopathy

Riad

Schwabedissen

Weitmann

et al. 2012

Journal of Biological Chemistry

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“…Thus, through mediation of endothelial actin cytoskeleton, TLR4 may be an important effector of IRI-induced edema in humans, and the TLR4 receptor may be a promising target for pharmacological intervention to mitigate IRI and other forms of acute lung injury. Pretreatment of mice with eritoran, another TLR4 inhibitor, reduced myocardial infarction size in a murine model of cardiac IRI (41). It is possible that CRX-526 may have effects on other receptors or pathways besides TLR4, but our in vivo data in HeJ and TLR4Ϫ/Ϫ mice clearly show that functional TLR4 substantially contributes to IRI-induced pulmonary edema.…”

Section: Discussionmentioning

confidence: 73%

Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema

Zanotti

Casiraghi

Abano³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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like receptors (TLRs) of the innate immune system contribute to noninfectious inflammatory processes. We employed a murine model of hilar clamping (1 h) with reperfusion times between 15 min and 3 h in TLR4-sufficient (C3H/ OuJ) and TLR4-deficient (C3H/HeJ) anesthetized mice with additional studies in chimeric and myeloid differentiation factor 88 (MyD88)-and TLR4-deficient mice to determine the role of TLR4 in lung ischemia-reperfusion injury. Human pulmonary microvascular endothelial monolayers were subjected to simulated warm ischemia and reperfusion with and without CRX-526, a competitive TLR4 inhibitor. Functional TLR4 solely on pulmonary parenchymal cells, not bone marrow-derived cells, mediates early lung edema following ischemia-reperfusion independent of MyD88. Activation of MAPKs and NF-B was significantly blunted and/or delayed in lungs of TLR4-deficient mice as a consequence of ischemia-reperfusion injury, but edema development appeared to be independent of activation of these signaling pathways. Pretreatment with a competitive TLR4 inhibitor prevented edema in vivo and reduced actin cytoskeletal rearrangement and gap formation in pulmonary microvascular endothelial monolayers subjected to simulated warm ischemia and reperfusion. In addition to its well-accepted role to alter gene transcription, functioning TLR4 on pulmonary parenchymal cells plays a key role in very early and profound pulmonary edema in murine lung ischemiareperfusion injury. This may be due to a novel mechanism: regulation of endothelial cell cytoskeleton affecting microvascular endothelial cell permeability. microvascular permeability; endothelial cell; pulmonary edema ACUTE LUNG INJURY IS A FEATURE of sepsis, systemic inflammatory response, and adult respiratory distress syndrome. Noncardiogenic pulmonary edema and impaired gas exchange are consequences of acute lung injury, irrespective of etiology. The mechanisms causing pulmonary edema due to acute lung injury are not well-understood. Ischemia-reperfusion injury (IRI), a form of acute lung injury occurring immediately following lung transplantation, is a frequent complication causing morbidity and mortality (26). A greater understanding of lung IRI is likely relevant to many types of acute lung injury and thus may benefit not only lung transplant recipients, but also substantial numbers of other patients with lung injury. Such knowledge would also facilitate retrieval of lungs from nonheart-beating cadaver donors for transplant and/or may assist in the salvage of lungs not considered suitable for transplant, thereby reducing the critical shortage of transplantable lungs (8, 11).Reperfusion following an interval of ischemia results in an inflammatory response involving components of the innate immune system, including the complement and coagulation cascades. Both parenchymal and myeloid cells elaborate free radicals, nitric oxide, and pro-and anti-inflammatory cytokines (4, 5). Recently, there has been increasing awareness of the important contribution of the innate immune syst...

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“…Moreover, Michelsen et al showed that lack of TLR4 results in reduction of atherosclerosis in mice [29]. A study showed that direct inhibition of TLR4 could significantly reduce the detrimental effects of myocardial ischemia reperfusion [30]. Those findings were further supported by the point, thath TLR4 deficiency leads to alteration in lipid content of atherosclerotic plaque and reduces macrophage infiltration.…”

Section: Discussionmentioning

confidence: 94%

Association of monoctye expression of Toll-like receptor 4 and its related cytokines with coronary luminal stenosis

Bagheri¹,

Sohrabi²,

Movassaghpur³

et al. 2013

ABB

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Toll-like receptors are well-defined barriers in innate immunity. Among them hTLR4 on the surface of monocytes, plays a critical role in the formation of atherosclerotic plaques, plaque instability and arterial remodeling through production of inflammatory cytokines. This study was designed to examine the association of hTLR4 monocyte expression and response with the severity of coronary stenosis in patients with stable angina (SA). Blood samples were obtained from 39 patients with SA who were scheduled for a coronary angiography and from 28 healthy volunteers. The samples were collected before the procedure. Expression of hTLR4 on CD14 + monocytes and serum levels of TNF-α and IL-1β were measured using flowcytometry and ELISA techniques respectively. Percentage stenosis diameter was measured by comparing the area of coronary stenosis to an adjacent normal segment of the vessel. Compared with control group, patients showed upregulation of hTLR4 + /CD14 + monocytes. Furthermore, patients with more severe coronary stenosis exhibited enhanced expression of hTLR4 + /CD14 + monocytes (p < 0.01). This was paralleled by elevation in the serum levels of TNF-α (p < 0.05) and IL-1β. In addition, significant correlations were seen between percentage stenosis diameter and monocyte expression of hTLR4 as well as TNF-α. hTLR4 monocytic expression and related cytokines are positively associated percentage stenosis diameter. These results suggest that hTLR4 activity may be involved in progression of atherosclerosis.

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Inhibition of Toll-like Receptor 4 With Eritoran Attenuates Myocardial Ischemia-Reperfusion Injury

Cited by 238 publications

References 24 publications

Variants of Toll-like Receptor 4 Predict Cardiac Recovery in Patients with Dilated Cardiomyopathy

Variants of Toll-like Receptor 4 Predict Cardiac Recovery in Patients with Dilated Cardiomyopathy

Novel critical role of Toll-like receptor 4 in lung ischemia-reperfusion injury and edema

Association of monoctye expression of Toll-like receptor 4 and its related cytokines with coronary luminal stenosis

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