Hemorrhage-induced acute lung injury is TLR-4 dependent

Barsness, Katherine A.; Arcaroli, John J.; Harken, Alden H.; Abraham, Edward; Banerjee, Anirban; Reznikov, Leonid L.; McIntyre, Robert C.

doi:10.1152/ajpregu.00412.2003

Cited by 122 publications

(94 citation statements)

References 52 publications

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“…Previous studies suggested that TLR4 participates in the pathogenesis of non-infectious lung injury. TLR4 recognizes diesel exhaust particles (Inoue et al, 2006) and pollutant ozone (Kleeberger et al, 2010), expressed in smoke-induced lung injury (Karimi et al, 2006), and is required for hemorrhage-induced lung tumor necrosis factor-α production, neutrophil accumulation, and protein permeability (Barsness et al, 2004), supporting that TLR4 accelerates the progress of non-infectious lung disease. However, TLR4 maintained appropriate levels of anti-apoptotic responses during oxidant stress, and thus played a protective role in oxidant-mediated lung injury (Zhang et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4 promotes fibrosis in bleomycin-induced lung injury in mice

Li¹,

Jiang²,

Huang³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The specific role of Toll-like receptor 4 (TLR4) in bleomycininduced lung fibrosis of mice, a model of human idiopathic pulmonary fibrosis, has not been characterized. We injected bleomycin intratracheally into TLR4 knockout (TLR4 -/-) and wild-type (WT) mice. Twenty-one days after injection, mice were sacrificed and their lungs were harvested for pathological, hydroxyproline, mRNA expression, and collagen I analyses. Body weight changes and mortality were observed. Light microscopy showed that lung fibrosis was minimal in TLR4-/-compared to that in WT mice on day 21 after bleomycin instillation. The Ashcroft score was significantly lower in TLR4 -/-than in WT mice (3.667 ± 0.730 vs 4.945 ± 0.880, P < 0.05). Hydroxyproline content was significantly lower in TLR4-/-than in WT mice on day 21 after bleomycin injection (0.281 ± 0.022 vs 0.371 ± 0.047, P < 0.05). Compared to WT mice, bleomycin-treated TLR4 -/-mice expressed significantly lower type I collagen mRNA levels (mesenchymal marker; 11.069 ± 2.627 vs 4.589 ± 1.440, P < 0.05). Collagen I was significantly lower in TLR4 -/-than in WT mice (0.838 ± 0.352 vs 2.427 ± 0.551, P < 0.05). Bleomycin-treated TLR4 -/-mice had a significantly lower mortality rate on day 21 than WT mice (33 vs 75%, P < 0.05). Body weight reduction was lower in TLR4 -/-mice than in WT mice; this difference was not statistically significant (-3.735 ± 5.276 vs -6.698 ± 3.218, P > 0.05). Thus, bleomycininduced pulmonary fibrosis is TLR4-dependent and TLR4 promoted fibrosis in bleomycin-challenged mice.

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Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4 promotes fibrosis in bleomycin-induced lung injury in mice

Li¹,

Jiang²,

Huang³

et al. 2015

Genet. Mol. Res.

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“…by ischemia-reperfusion (29) or in hemorrhage-induced acute lung injury (30)). However, efficient inhibitors of TLR4 activation in inflammatory conditions are not yet in therapeutic use, although several of them are at the advanced stages of clinical trials (31).…”

Section: Discussionmentioning

confidence: 99%

Free Thiol Group of MD-2 as the Target for Inhibition of the Lipopolysaccharide-induced Cell Activation

Manček-Keber

Gradišar

Pestaña

et al. 2009

Journal of Biological Chemistry

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MD-2 is a part of the Toll-like 4 signaling complex with an indispensable role in activation of the lipopolysaccharide (LPS) signaling pathway and thus a suitable target for the therapeutic inhibition of TLR4 signaling. Elucidation of MD-2 structure provides a foundation for rational design of inhibitors that bind to MD-2 and inhibit LPS signaling. Since the hydrophobic binding pocket of MD-2 provides little specificity for inhibitors, we have investigated targeting the solvent-accessible cysteine residue within the hydrophobic binding pocket of MD-2. Compounds with affinity for the hydrophobic pocket that contain a thiol-reactive group, which mediates covalent bond formation with the free cysteine residue of MD-2, were tested. Fluorescent compounds 2-(4-(iodoacetamido)anilino)naphthalene-6-sulfonic acid and N-pyrene maleimide formed a covalent bond with MD-2 through Cys 133 and inhibited LPS signaling. Cell activation was also inhibited by thiol-reactive compounds JTT-705 originally targeted against cholesterol ester transfer protein and antirheumatic compound auranofin. Oral intake of JTT-705 significantly inhibited endotoxin-triggered tumor necrosis factor ␣ production in mice. The thiol group of MD-2 also represents the target of environmental or endogenous thiol-reactive compounds that are produced in inflammation. TLR4 is a receptor for lipopolysaccharide (LPS)4 a major constituent of outer membrane of Gram-negative bacteria. MD-2 is the final LPS-binding protein in the recognition cascade before TLR4 transmits the signal across the cell membrane to activate the inflammatory response. MD-2 binds to the ectodomain of TLR4 and binds LPS either alone or in complex with TLR4 (1, 2). Mice deficient in MD-2 survive endotoxic shock (3). MD-2 has been indispensable in almost all investigated conditions of TLR4-triggered inflammation; therefore, it could represent the "Achilles' heel" of the inflammatory response to LPS and a target for a pharmacological intervention in endotoxemia as well as other conditions involving cell activation mediated by TLR4 (4, 5). The existence of a single free cysteine residue among the seven cysteine residues has been predicted from MD-2 mutagenesis (6, 7) and molecular modeling proposed that Cys 133 lies in the hydrophobic pocket (8, 9). The hydrophobic binding site of MD-2 was also mapped by an apolar probe, bis-ANS, which does not contain acyl chains as most LPS antagonists yet preserves the characteristic structural motif of lipid A, consisting of a hydrophobic region and a pair of separated negatively charged groups (10). Crystal structures of MD-2 with bound eritoran or lipid IVa confirmed the location of Cys 133 in the hydrophobic pocket in close vicinity of bound lipid A derivatives (11, 12). The free cysteine residue inside the binding pocket can thus be a target for irreversible inhibition of MD-2 activity. An inhibitory mechanism based on a covalent modification of a free cysteine residue in the active or binding site of a protein has been demonstrated for other proteins, s...

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“…(iii) In tissue injury and repair, several recent studies examined the expression patterns of TLR2 and/or TLR4 in smoke-induced lung injury and in patients with chronic obstructive pulmonary disease [63][64][65]. Hemorrhage-induced lung TNF-a production, neutrophil accumulation, and protein permeability, but not NF-kB activation, were dependent on a functional TLR4 [66]. TLR4-TLR2 cross-talk activated a positive-feedback signal leading to alveolar macrophage priming and exaggerated lung inflammation in response to invading pathogens during hemorrhage-induced acute lung injury [67].…”

Section: Toll-like Receptorsmentioning

confidence: 99%

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

et al. 2006

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The role of Toll-like receptors (TLRs) in pathogen recognition has been expeditiously advanced in recent years. However, investigations into the function of TLRs in non-infectious tissue injury have just begun. Previously, we and others have demonstrated that fragmented hyaluronan (HA) accumulates during tissue injury. CD44 is required to clear HA during tissue injury, and impaired clearance of HA results in unremitting inflammation. Additionally, fragmented HA stimulates the expression of inflammatory genes by inflammatory cells at the injury site. Recently, we identified that HA fragments require both TLR2 and TLR4 to stimulate mouse macrophages to produce inflammatory chemokines and cytokines. In a non-infectious lung injury model, mice deficient in both TLR2 and TLR4 show an impaired transepithelial migration of inflammatory cells, increased tissue injury, elevated lung epithelial cell apoptosis, and decreased survival. Lung epithelial cell overexpression of high molecular mass HA protected mice against acute lung injury and apoptosis, in part through TLR-dependent basal activation of NF-kB. The exaggerated injury in TLR2 and TLR4 deficient mice appears to be due to impaired HA-TLR interactions on epithelial cells. These studies identify that host matrix component HA and TLR interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from acute lung injury.

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Hemorrhage-induced acute lung injury is TLR-4 dependent

Cited by 122 publications

References 52 publications

Toll-like receptor 4 promotes fibrosis in bleomycin-induced lung injury in mice

Toll-like receptor 4 promotes fibrosis in bleomycin-induced lung injury in mice

Free Thiol Group of MD-2 as the Target for Inhibition of the Lipopolysaccharide-induced Cell Activation

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

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