Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model

Villar, Jesús; Cabrera, Nuria E.; Casula, Milena; Flores, Carlos; Valladares, Francisco; Muros, Mercedes; Blanch, Lluís; Slutsky, Arthur S.; Kacmarek, Robert M.

doi:10.1007/s00134-010-1799-3

Cited by 46 publications

(46 citation statements)

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“…m. for 7 min using a protocol described previously by our group. 5 Protein concentrations in extracts were determined with the Bio-Rad DC protein assay (Bio-Rad DC, Hercules, CA, USA). For immunoblotting, 30 μg of samples were electrophoresed and transferred to polyvinylidene difluoride (PVDF) membranes, blocked for 1 h at room temperature, and probed with primary antibodies to TLR4, IκBα, Bax, Bcl-2, caspase-3, and β-actin in all experimental groups (see ESM for details).…”

Section: Western Blot Analysismentioning

confidence: 99%

“…Eventually, the NF-κB system exerts transcriptional regulation on the expression of genes related to innate immunity and inflammation, and other gene products. 5 LPS can induce apoptosis in lung endothelial and epithelial cells 6,7 and contributes to the pathogenesis of ARDS. Recent studies strongly suggested a role for epithelial apoptosis as a key profibrotic event in lung fibrogenesis.…”

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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: Western Blot Analysismentioning

confidence: 99%

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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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“…In this month's issue of Intensive Care Medicine, Villar et al [12] present the results of an experimental study aimed at determining the impact of MV on lung inflammation in animals with previous abdominal sepsis and surgery, a classical ''two-hit'' model of ventilator-induced lung injury. A caecal ligation and puncture was performed in previously healthy rats.…”

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Toll-like receptors: a link between mechanical ventilation, innate immunity and lung injury?

Charles

Barbar

2010

Intensive Care Med

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“…This included blocking/reducing activation of the innate immune system elicited by exposure to Toll-like receptor (TLR) ligands, and effect that persisted for up to 1 week in vivo. Of interest, evidence suggests that the immune activation induced by MV is at least partially mediated via TLRs 9 and 4 (46,47). This work utilized the lung protective ventilator setting typically employed when MV is administered to patients.…”

Section: Discussionmentioning

confidence: 99%

Suppressive oligonucleotides inhibit inflammation in a murine model of mechanical ventilator induced lung injury

Scheiermann¹,

Klinman²

2016

J. Thorac. Dis.

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Mechanical ventilation modulates Toll-like receptor signaling pathway in a sepsis-induced lung injury model

Abstract: Our findings suggest a novel mechanism that could partially explain how MV modulates the innate immune response in the lung by interfering with cellular signaling pathways that are activated in response to pathogens.

Cited by 46 publications

References 47 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

Toll-like receptors: a link between mechanical ventilation, innate immunity and lung injury?

Suppressive oligonucleotides inhibit inflammation in a murine model of mechanical ventilator induced lung injury

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