Abstract
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.
Highlights
Mechanical ventilation (MV) could prime the lung toward an inflammatory response if exposed to another insult such as bacterial invasion
Cyclic stretch increases the inflammatory response of lung epithelial cells to bacterial lipopeptide A549 cells submitted to a 24-hour stretch released higher levels of IL-6 and IL-8 in response to an additional 8-hour stimulation by the synthetic BLP Pam3CSK4 than did cells not submitted to cyclic stretch (Figure 3a)
Cyclic stretch-induced upregulation of TLR2 depends on the p38 mitogen-activated protein kinase (MAPK) signaling pathway To address the question of the signaling pathway by which cyclic stretch increased TLR2 mRNA, we tested the effects of a nuclear factor (NF)-B inhibitor (Sn50, 18 μM), and a p38 MAPK-specific inhibitor (SB203580, 1 μM) on cyclic stretch-induced IL-8 expression
Summary
Mechanical ventilation (MV) could prime the lung toward an inflammatory response if exposed to another insult such as bacterial invasion. Toll-like receptors (TLRs) allow the host to recognize selectively bacterial pathogens and in turn to trigger an immune response. Bacterial superinfection of the lung is a frequent complication in critically ill patients requiring mechanical ventilation (MV) [1]. Among the pathogen recognition receptors, toll-like receptors (TLRs) play an indisputable and major role in the recognition of pathogen-associated microbial patterns. The ligation of TLRs by pathogen-associated molecular patterns induces the signaling of the subsequent inflammatory response. Bacterial lipopeptides (BLPs) are cell wall components of both Gram-positive and Gram-negative bacteria and have been recognized to activate TLR2 in a heterodimeric association with TLR1 or TLR6 [12,13]
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