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Association of Toll-like receptor signaling and reactive oxygen species: a potential therapeutic target for posttrauma acute lung injury.

Xiang M, Fan J, Fan J - Mediators Inflamm. (2010)

Bottom Line: Hemorrhagic shock (HS) that results from major trauma promotes the development of SIRS and ALI by priming the innate immune system for an exaggerated inflammatory response.Recent studies have reported that the mechanism underlying the priming of pulmonary inflammation involves the complicated cross-talk between Toll-like receptors (TLRs) and interactions between neutrophils (PMNs) and alveolar macrophages (AMvarphi) as well as endothelial cells (ECs), in which reactive oxygen species (ROS) are the key mediator.This paper summarizes some novel mechanisms underlying HS-primed lung inflammation focusing on the role of TLRs and ROS, and therefore suggests a new therapeutic target for posttrauma ALI.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.

ABSTRACT
Acute lung injury (ALI) frequently occurs in traumatic patients and serves as an important component of systemic inflammatory response syndrome (SIRS). Hemorrhagic shock (HS) that results from major trauma promotes the development of SIRS and ALI by priming the innate immune system for an exaggerated inflammatory response. Recent studies have reported that the mechanism underlying the priming of pulmonary inflammation involves the complicated cross-talk between Toll-like receptors (TLRs) and interactions between neutrophils (PMNs) and alveolar macrophages (AMvarphi) as well as endothelial cells (ECs), in which reactive oxygen species (ROS) are the key mediator. This paper summarizes some novel mechanisms underlying HS-primed lung inflammation focusing on the role of TLRs and ROS, and therefore suggests a new therapeutic target for posttrauma ALI.

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Related in: MedlinePlus

Role of PMN NADPH oxidase-derived oxidant signaling in mediating the TLR4-TLR2 cross talk in ECs.  LPS stimulation induces NADPH oxidase activation and production of reactive oxygen species (ROS) in PMN as well as the initiation of MyD88-dependent NF-κB signaling in ECs and the consequent expression of TLR2 and ICAM-1.  Adhesion of PMN to ECs is mediated by the binding of constitutive ICAM-1 to CD18 integrin and provides the appropriate coupling required for PMN to transmit oxidant signals to ECs.  The oxidants augment NF-κB signaling and TLR2 expression (+), which result in the augmented response of the cell to PGN, thereby amplifying ICAM-1 expression (circled +) and promoting stable adhesion of PMN to ECs and increased PMN migration.  Thus, the PMN NADPH oxidase-mediated TLR4-TLR2 cross talk activates a positive feedback signal leading to sustained and amplified endothelial activation in response to invading pathogens.
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fig4: Role of PMN NADPH oxidase-derived oxidant signaling in mediating the TLR4-TLR2 cross talk in ECs. LPS stimulation induces NADPH oxidase activation and production of reactive oxygen species (ROS) in PMN as well as the initiation of MyD88-dependent NF-κB signaling in ECs and the consequent expression of TLR2 and ICAM-1. Adhesion of PMN to ECs is mediated by the binding of constitutive ICAM-1 to CD18 integrin and provides the appropriate coupling required for PMN to transmit oxidant signals to ECs. The oxidants augment NF-κB signaling and TLR2 expression (+), which result in the augmented response of the cell to PGN, thereby amplifying ICAM-1 expression (circled +) and promoting stable adhesion of PMN to ECs and increased PMN migration. Thus, the PMN NADPH oxidase-mediated TLR4-TLR2 cross talk activates a positive feedback signal leading to sustained and amplified endothelial activation in response to invading pathogens.

Mentions: ROS also contribute to LPS/TLR4 signaling induced TLR2 expression in lung EC [28]. LPS through TLR4-MyD88-dependent signaling activated NF-κB and induced TLR2 expression in ECs, and this process was enhanced by oxidant signaling generated by PMN NADPH oxidase. The functional relevance of NADPH oxidase in mediating TLR4-induced TLR2 expression in ECs was evident by markedly elevated and stable ICAM-1 expression as well as augmented PMN migration in response to sequential challenge with LPS and PGN (Figure 4) [28].


Association of Toll-like receptor signaling and reactive oxygen species: a potential therapeutic target for posttrauma acute lung injury.

Xiang M, Fan J, Fan J - Mediators Inflamm. (2010)

Role of PMN NADPH oxidase-derived oxidant signaling in mediating the TLR4-TLR2 cross talk in ECs.  LPS stimulation induces NADPH oxidase activation and production of reactive oxygen species (ROS) in PMN as well as the initiation of MyD88-dependent NF-κB signaling in ECs and the consequent expression of TLR2 and ICAM-1.  Adhesion of PMN to ECs is mediated by the binding of constitutive ICAM-1 to CD18 integrin and provides the appropriate coupling required for PMN to transmit oxidant signals to ECs.  The oxidants augment NF-κB signaling and TLR2 expression (+), which result in the augmented response of the cell to PGN, thereby amplifying ICAM-1 expression (circled +) and promoting stable adhesion of PMN to ECs and increased PMN migration.  Thus, the PMN NADPH oxidase-mediated TLR4-TLR2 cross talk activates a positive feedback signal leading to sustained and amplified endothelial activation in response to invading pathogens.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2913855&req=5

fig4: Role of PMN NADPH oxidase-derived oxidant signaling in mediating the TLR4-TLR2 cross talk in ECs. LPS stimulation induces NADPH oxidase activation and production of reactive oxygen species (ROS) in PMN as well as the initiation of MyD88-dependent NF-κB signaling in ECs and the consequent expression of TLR2 and ICAM-1. Adhesion of PMN to ECs is mediated by the binding of constitutive ICAM-1 to CD18 integrin and provides the appropriate coupling required for PMN to transmit oxidant signals to ECs. The oxidants augment NF-κB signaling and TLR2 expression (+), which result in the augmented response of the cell to PGN, thereby amplifying ICAM-1 expression (circled +) and promoting stable adhesion of PMN to ECs and increased PMN migration. Thus, the PMN NADPH oxidase-mediated TLR4-TLR2 cross talk activates a positive feedback signal leading to sustained and amplified endothelial activation in response to invading pathogens.
Mentions: ROS also contribute to LPS/TLR4 signaling induced TLR2 expression in lung EC [28]. LPS through TLR4-MyD88-dependent signaling activated NF-κB and induced TLR2 expression in ECs, and this process was enhanced by oxidant signaling generated by PMN NADPH oxidase. The functional relevance of NADPH oxidase in mediating TLR4-induced TLR2 expression in ECs was evident by markedly elevated and stable ICAM-1 expression as well as augmented PMN migration in response to sequential challenge with LPS and PGN (Figure 4) [28].

Bottom Line: Hemorrhagic shock (HS) that results from major trauma promotes the development of SIRS and ALI by priming the innate immune system for an exaggerated inflammatory response.Recent studies have reported that the mechanism underlying the priming of pulmonary inflammation involves the complicated cross-talk between Toll-like receptors (TLRs) and interactions between neutrophils (PMNs) and alveolar macrophages (AMvarphi) as well as endothelial cells (ECs), in which reactive oxygen species (ROS) are the key mediator.This paper summarizes some novel mechanisms underlying HS-primed lung inflammation focusing on the role of TLRs and ROS, and therefore suggests a new therapeutic target for posttrauma ALI.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA.

ABSTRACT
Acute lung injury (ALI) frequently occurs in traumatic patients and serves as an important component of systemic inflammatory response syndrome (SIRS). Hemorrhagic shock (HS) that results from major trauma promotes the development of SIRS and ALI by priming the innate immune system for an exaggerated inflammatory response. Recent studies have reported that the mechanism underlying the priming of pulmonary inflammation involves the complicated cross-talk between Toll-like receptors (TLRs) and interactions between neutrophils (PMNs) and alveolar macrophages (AMvarphi) as well as endothelial cells (ECs), in which reactive oxygen species (ROS) are the key mediator. This paper summarizes some novel mechanisms underlying HS-primed lung inflammation focusing on the role of TLRs and ROS, and therefore suggests a new therapeutic target for posttrauma ALI.

Show MeSH
Related in: MedlinePlus