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

Abstract

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...

Research on WISP1 in Lung Disease

“…TLR4 has been shown to play a critical role in ALI induced by high tidal volume mechanical ventilation (HTV), [82,84,85], LPS [86], acid aspiration [87], hemorrhage [88], and ischemia and reperfusion injury [89]. Hu et al [84] showed that HTV increases WISP1 expression [84]; meanwhile, mechanical stretch has been demonstrated to increase endogenous TLR4 ligand production and activate TLR4 in healthy mice [90,91].…”

Therapeutic strategies in pneumonia: going beyond antibiotics

“…For example, Toll-like receptor (TLR)4 was shown to contribute to the regulation of vascular permeability [23][24][25][26][27]. Therefore, the development of the synthetic TLR4 antagonist eritoran to suppress TLR4/MD2-mediated signalling was highly promising.…”

The pro-inflammatory role of high-mobility group box 1 protein (HMGB-1) in photoreceptors and retinal explants exposed to elevated pressure

“…[36][37][38][39][40][41] The mechanism underlying inflammation involves binding to TLR-4, which mediates the HMGB-1-dependent activation of macrophage cytokine release. 42 The study promotes the upregulation of RAGE, TLR-2, and TLR-4 in 661W cells as well as retinal explants exposed to elevated pressure.…”