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

Charles, Pierre‐Emmanuel; Barbar, Saber Davide

doi:10.1007/s00134-010-1804-x

Cited by 5 publications

(6 citation statements)

References 23 publications

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“…These results are reminiscent of those found with the LPS/CD14/TLR4 pathway [3-6,24], and highlight the increased reactivity of lung cells to Gram-positive bacterial products and bacteria induced by MV via the TLR2 pathway [25,26]. Moreover, in contrast with previous findings, we observed that TLR2 and TLR4 could be differentially upregulated by cyclic stretch.…”

Section: Discussionsupporting

confidence: 67%

Mild-stretch mechanical ventilation upregulates toll-like receptor 2 and sensitizes the lung to bacterial lipopeptide

et al. 2011

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IntroductionMechanical ventilation (MV) could prime the lung toward an inflammatory response if exposed to another insult such as bacterial invasion. The underlying mechanisms are not so far clear. Toll-like receptors (TLRs) allow the host to recognize selectively bacterial pathogens and in turn to trigger an immune response. We therefore hypothesized that MV modulates TLR2 expression and in turn modifies responsiveness to agonists such as bacterial lipopeptide (BLP).MethodBoth in vitro and in vivo experiments were conducted. First, TLR2 expression and protein were measured in the A549 pulmonary epithelial cell line submitted to 8-hour cyclic stretch (20% elongation; 20/minute rate). After a 24-hour period of cyclic stretch, the inflammatory response of the A549 cells to the synthetic BLP, Pam3CSK4, was tested after 8 hours of exposure. In a second set of experiments, healthy anesthetized and paralyzed rabbits were submitted to 8-hour MV (tidal volume = 12 ml/kg, zero end-expiratory pressure; FIO2 = 50%; respiratory rate = 20/minute) before being sacrificed for TLR2 lung expression assessment. The lung inflammatory response to BLP was then tested in animals submitted to 24-hour MV before being sacrificed 8 hours after the tracheal instillation of Pam3CSK4.ResultsCyclic stretch of human pulmonary epithelial cell lines increased both TLR2 mRNA and protein expression. Cells submitted to cyclic stretch also increased IL-6 and IL-8 secretion in response to Pam3CSK4, a classical TLR2 ligand. A mild-stretch MV protocol induced a 60-fold increase of TLR2 mRNA expression in lung tissue when compared with spontaneously breathing controls. Moreover, the combination of MV and airway exposure to Pam3CSK4 acted synergistically in causing lung inflammation and injury.ConclusionsMild-stretch MV increases lung expression of TLR2 and sensitizes the lung to bacterial TLR2 ligands. This may account for the propensity of mechanically ventilated patients to develop acute lung injury in the context of airway bacterial colonization/infection.

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Section: Discussionsupporting

confidence: 67%

Mild-stretch mechanical ventilation upregulates toll-like receptor 2 and sensitizes the lung to bacterial lipopeptide

et al. 2011

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“…Synergistic interactions of bacterial products and MV, even in conventional tidal volumes, for lung injury have been reported [ 47 , 48 ]. Indeed, cooperation and synergism for transcriptional factors is currently thought to be the underlying molecular mechanism that causes the combined effect of the two insults [ 22 ]. Mitogen-activated protein kinase (MAPK) pathways and nuclear factor kappa B (NF-κB) activation contribute to inflammatory responses in CDI [ 49 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mitogen-activated protein kinase (MAPK) pathways and nuclear factor kappa B (NF-κB) activation contribute to inflammatory responses in CDI [ 49 ]. Interestingly, cell stretching in MV can activate similar signaling pathways (MAPK, NF-κB) as CDI to produce proinflammatory cytokines [ 22 ]. Moreover, activating the innate immune sensors, or pattern-recognition receptors (Toll-like receptor family: TLR-2, TLR-4, and TLR-5), is important for developing CDI [ 16 , 50 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, MV not only initiates lung injury and inflammation, but it also leads to a spillover of the inflammatory mediators from the lungs into the circulation, which propagates a systemic inflammatory response [ 19 , 20 ]. Significant inflammatory responses of the lungs to mechanical stretching can also synergistically interact with a second insult, e.g., exposure to microbial agents or systemic inflammation [ 21 , 22 ] that harms extrapulmonary organs.…”

Section: Introductionmentioning

confidence: 99%

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Prolonged Mechanical Ventilation Assistance Interacts Synergistically with Carbapenem for Clostridium difficile Infection in Critically Ill Patients

Chiang

Lai

et al. 2018

JCM

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Objectives: Interactions between mechanical ventilation (MV) and carbapenem interventions were investigated for the risk of Clostridium difficile infection (CDI) in critically ill patients undergoing concurrent carbapenem therapy. Methods: Taiwan’s National Intensive Care Unit Database (NICUD) was used in this analytical, observational, and retrospective study. We analyzed 267,871 intubated patients in subgroups based on the duration of MV support: 7–14 days (n = 97,525), 15–21 days (n = 52,068), 22–28 days (n = 35,264), and 29–60 days (n = 70,021). The primary outcome was CDI. Results: Age (>75 years old), prolonged MV assistance (>21 days), carbapenem therapy (>15 days), and high comorbidity scores were identified as independent risk factors for developing CDI. CDI risk increased with longer MV support. The highest rate of CDI was in the MV 29–60 days subgroup (adjusted hazard ratio (AHR) = 2.85; 95% confidence interval (CI) = 1.46–5.58; p < 0.02). Moreover, higher CDI rates correlated with the interaction between MV and carbapenem interventions; these CDI risks were increased in the MV 15–21 days (AHR = 2.58; 95% CI = 1.12–5.91) and MV 29–60 days (AHR = 4.63; 95% CI = 1.14–10.03) subgroups than in the non-MV and non-carbapenem subgroups. Conclusions: Both MV support and carbapenem interventions significantly increase the risk that critically ill patients will develop CDI. Moreover, prolonged MV support and carbapenem therapy synergistically induce CDI. These findings provide new insights into the role of MV support in the development of CDI.

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“…Furthermore, due to the influence of a number of perioperative factors, certain cell functions can be modulated via ROS system [ 37 ]. The expression of toll-like receptors (TLRs) is also associated with mechanical induction of lung injury [ 38 , 39 ]. Previous studies have shown that signal transduction of TLRs can be modulated by sepsis [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

Mechanical Ventilation Induces an Inflammatory Response in Preinjured Lungs in Late Phase of Sepsis

Xuan

Zhou

Yao

et al. 2015

Oxidative Medicine and Cellular Longevity

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Mechanical ventilation (MV) may amplify the lung-specific inflammatory response in preinjured lungs by elevating cytokine release and augmenting damage to the alveolar integrity. In this study, we test the hypothesis that MV exerts different negative impacts on inflammatory response at different time points of postlung injury. Basic lung injury was induced by cecal ligation and puncture (CLP) surgery in rats. Physiological indexes including blood gases were monitored during MV and samples were assessed following each experiment. Low V T (tidal volume) MV caused a slight increase in cytokine release and tissue damage at day 1 and day 4 after sepsis induced lung injury, while cytokine release from the lungs in the two moderately ventilated V T groups was amplified. Interestingly, in the two groups where rats received low V T MV, we found that infiltration of inflammatory cells was only profound at day 4 after CLP. Marked elevation of protein leakage indicated a compromise in alveolar integrity in rats that received moderate V T MV at day 4 following CLP, correlating with architectural damage to the alveoli. Our study indicates that preinjured lungs are more sensitive to mechanical MV at later phases of sepsis, and this situation may be a result of differing immune status.

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

Cited by 5 publications

References 23 publications

Mild-stretch mechanical ventilation upregulates toll-like receptor 2 and sensitizes the lung to bacterial lipopeptide

Mild-stretch mechanical ventilation upregulates toll-like receptor 2 and sensitizes the lung to bacterial lipopeptide

Prolonged Mechanical Ventilation Assistance Interacts Synergistically with Carbapenem for Clostridium difficile Infection in Critically Ill Patients

Mechanical Ventilation Induces an Inflammatory Response in Preinjured Lungs in Late Phase of Sepsis

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