Role of Toll-like receptor 4 for the pathogenesis of acute lung injury in Gram-negative sepsis

Baumgarten, Georg; Knuefermann, Pascal; Wrigge, Hermann; Putensen, Christian; Stapel, Heidi; Fink, Klaus; Meyer, Rainer; Hoeft, Andreas; Grohé, Christian

doi:10.1017/s0265021506001098

Cited by 43 publications

(38 citation statements)

References 30 publications

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“…LPS initiates an inflammatory and immune defense response in the lung through recognition by TLR4. 4 Our results demonstrate that pyrrol compound DTA0118 inhibited changes in TLR4 and IκBα expression levels in human A549 and BEAS-2B cells stimulated by LPS, and this inhibition was much more effective than the effects produced by the reference compounds. Furthermore, DTA0118 significantly inhibited the synthesis of cytokines.…”

Section: Discussionmentioning

confidence: 57%

“…LPS has a crucial role in the inflammatory response triggered by Gram-negative bacteria in epithelial and other cells of the lung. Toll-like receptor-4 (TLR4) recognizes LPS and initiates a signaling cascade by several downstream adapter proteins that leads to the activation of nuclear factor-κB (NF-κB), 4 involving phosphorylation and degradation of the inhibitor of NF-κB (IκBα), and the translocation of NF-κB heterodimers into the nucleus of the cells. Eventually, the NF-κB system exerts transcriptional regulation on the expression of genes related to innate immunity and inflammation, and other gene products.…”

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confidence: 99%

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Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

Cabrera-Benítez

Pérez-Roth

Ramos-Nuez

et al. 2016

Laboratory Investigation

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Inflammation and apoptosis are crucial mechanisms for the development of the acute respiratory distress syndrome (ARDS). Currently, there is no specific pharmacological therapy for ARDS. We have evaluated the ability of a new family of 1,2,3,5-tetrasubstituted pyrrol compounds for attenuating lipopolysaccharide (LPS)-induced inflammation and apoptosis in an in vitro LPS-induced airway epithelial cell injury model based on the first steps of the development of sepsis-induced ARDS. Human alveolar A549 and human bronchial BEAS-2B cells were exposed to LPS, either alone or in combination with the pyrrol derivatives. Rhein and emodin, two representative compounds with proven activity against the effects of LPS, were used as reference compounds. The pyrrol compound that was termed DTA0118 had the strongest inhibitory activity and was selected as the lead compound to further explore its properties. Exposure to LPS caused an intense inflammatory response and apoptosis in both A549 and BEAS-2B cells. DTA0118 treatment downregulated Toll-like receptor-4 expression and upregulated nuclear factor-κB inhibitor-α expression in cells exposed to LPS. These anti-inflammatory effects were accompanied by a significantly lower secretion of interleukin-6 (IL-6), IL-8, and IL-1β. The observed antiapoptotic effect of DTA0118 was associated with the upregulation of antiapoptotic Bcl-2 and downregulation of proapoptotic Bax and active caspase-3 protein levels. Our findings demonstrate the potent anti-inflammatory and antiapoptotic properties of the pyrrol DTA0118 compound and suggest that it could be considered as a potential drug therapy for the acute phase of sepsis and septic ARDS. Further investigations are needed to examine and validate these mechanisms and effects in a clinically relevant animal model of sepsis and sepsis-induced ARDS.

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Section: Discussionmentioning

confidence: 57%

mentioning

confidence: 99%

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

Cabrera-Benítez

Pérez-Roth

Ramos-Nuez

et al. 2016

Laboratory Investigation

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“…High mobility group box 1, a transcriptional regulator protein, previously implicated in late endotoxin lethality, appears to be involved in toxic and environmental chemical-induced ALI [56]. Toll-like receptor 4 signalling appears to regulate pro-inflammatory cytokines, such as NF-kB, interleukin (IL)-1b and -6, induced by LPS in mice [57]. The antioxidant flavonoid hesperidin has immunomodulatory properties, and in a murine model of LPS-induced ARDS, successfully inhibited the expression of a number of pro-inflammatory mediators, including IL-8, tumour necrosis factor (TNF)-a, IL-1b, IL-6, IL-12, intercellular adhesion molecule-1 and vascular cellular adhesion molecule-1 [58].…”

Section: Biotraumamentioning

confidence: 99%

Ventilator-associated lung injury: a search for better therapeutic targets

Oeckler¹,

Hubmayr²

2007

European Respiratory Journal

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) represent a continuum of injury that may arise from a number of primary insults.Localised injury may progress due to trauma from mechanical ventilation, a finding that has led to intense debate in the clinical and experimental literature over optimal ventilator management. The implementation of low tidal volume strategies has led to an improvement in outcomes; however, mortality remains unacceptably high.In the current review, ventilator-associated lung injury is examined, as it relates to the pathophysiological changes beyond direct airway trauma in ALI and ARDS, and an attempt is made to provide a historical perspective to outline potential current and future pitfalls in the use of surrogate end-points and the discovery of potential biomarkers. The systemic responses that lead to multi-organ dysfunction, the leading causes of morbidity and mortality in ALI and ARDS, are caused by pro-inflammatory signalling cascades and the activation of such diverse mediators as reactive oxygen species, immune response elements, apoptotic constituents and coagulation proteins.These areas are examined, including key mediators, and possible future areas of interest are discussed, including the potential of an ''acute lung injury chip'' to integrate measured surrogate biomarkers with real-time clinical information to improve patient outcomes.

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“…It is a common cause of acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS). [11,12] ALI and ARDS are the major causes of death caused by sepsis induced by gram-negative bacterial infections. A large number of pro-inflammatory cytokines can lead to pulmonary vascular endothelial injury and increased pulmonary vascular permeability, which are important causes of lung injury.…”

Section: Discussionmentioning

confidence: 99%

Expression of high mobility group protein B1 in the lungs of rats with sepsis

Qiu

Tang

et al. 2011

World Journal of Emergency Medicine

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BACKGROUND:Vibrio vulnifi cus inside the body could activate the NF-κB signaling pathway and initiate the inflammatory cascade. The lung is one of the earliest organs affected by sepsis associated with acute lung injury. High mobility group protein B1 (HMGB1) is an important late-acting pro-infl ammatory cytokine involving in the pathophysiology of sepsis. It is also involved in the injury process in the lung, liver and intestine. There has been no report on the involvement of HMGB1 in Vibrio vulnifi cus sepsis-induced lung injury.METHODS: Sixty rats were randomly divided into a normal control group (group A, n=10) and a Vibrio vulnificus sepsis group (group B, n=50). Sepsis was induced in the rats by subcutaneous injection of Vibrio vulnificus (concentration 6×10 8 cfu/mL, volume 0.1 mL/100g)) into the left lower limbs. The rats in group B were sacrifi ced separately 1, 6, 12, 24, and 48 hours after the infection. Their lungs were stored as specimens, lung water content was measured, and lung pathology was observed under a light microscope. The expressions of the HMGB1 gene and protein in the lungs were detected by RT-PCR and Western blot. Data were analyzed with one-way analysis of variance (ANOVA) and the LSD method for pair-wise comparison between the two groups. P<0.05 was considered statistically signifi cant.

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Role of Toll-like receptor 4 for the pathogenesis of acute lung injury in Gram-negative sepsis

Abstract: Our findings suggest that TLR4 plays a key role for regulating the expression of relevant cytokines within the lung during endotoxic shock.

Cited by 43 publications

References 30 publications

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

Inhibition of endotoxin-induced airway epithelial cell injury by a novel family of pyrrol derivates

Ventilator-associated lung injury: a search for better therapeutic targets

Expression of high mobility group protein B1 in the lungs of rats with sepsis

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