6533b7d1fe1ef96bd125d3a0

RESEARCH PRODUCT

Analysis and modulation of the inflammatory response through lung agression related to bacterial infection and mechanical ventilation

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description

Despite major advances since decades in the management of ventilated patients, ventilator-associated pneumonia (VAP) continues to complicate the course of approximately 28% of the patients receiving mechanical ventilation (MV). Among patients hospitalized in intensive care units, the risk of pneumonia is 3- to 10- fold increased in MV patients. However, MV is often the only way to care for critically ill patients with respiratory failure. It has now been clearly demonstrated that MV, in particular adverse ventilatory strategies could activate lung cells, thus leading to a proinflammatory response, even in the absence of pathogen. This is the biotrauma paradigm, which accounts, at least in part, for the ventilator induced lung injury (VILI). In one way, MV primes airway cells to respond massively to a second proinflammatory insult, through the subsequent release of large amounts of cytokines (as interleukin (IL)‐ 8), thus leading to additional lung injury, particularly through the recruitment of neutrophils attracted by the massive release of IL-8. Accordingly, innate immunity plays an important role in the developement of VILI. The involvement of Toll-like receptors has been suggested by several experimental studies. Ventilation in the prone position (PP) has been described to have beneficial effects on patients under MV, especially in those with lobar involvement. Our team focused particularly on the TLR2, which interacts with Gram-positive bacteria, and we have previously demonstrated in vitro that cyclic stretch of human pulmonary cells resulted in TLR2 overexpression and enhanced TLR2 reactivity to Gram-positive cell wall components. We confirmed these datas in an in vivo model of ventilated rabbits which immune response had been stimulated with Pam3CSK4. In a first project, we assessed the impact of the PP on unilateral pneumonia to Enterobacter aerogenes in rabbits subjected to MV. Our results shows that the prone position could be protective if the host is subjected to MV and unilateral bacterial pneumonia. To ensure the relevance of our hypothesis on TLR2 in our animal model of VAP, we conducted experiments using live bacteria specifically recognized by TLR2 (Methicilin resist. aureus). We demonstrate that mild-­‐stretch MV impaired lung bacterial clearance, hastened tissue injury and promoted a systemic inflammatory response. Both pulmonary and peripheral blood TLR2 overexpression could account for such an impact. The third project assessed the impact of a statins therapy in the context of MRSA VAP, treated with linezolid, in our model of ventilated rabbits. Our results suggest that statin exposure prior to pneumonia provides an anti-­‐inflammatory effect within the lung and the systemic compartment of rabbits with MRSA VAP. Although LNZ enhances pulmonary bacterial clearance, dampening the host systemic inflammatory response with statin could impede defense against MRSA in this compartment. It could be subsequent to enhanced antibacterial defences and improvements in lung mechanics, thereby blunting overwhelming inflammation. In the last project, in collaboration with the University of Geneva, we assessed whether mitochondrial alarmins are released during VILI and can generate lung inflammation. Our results confirmed the hypothesis made and showed indeed that alarmins are released during during cyclic stretch of human epithelial cells, as well as in BAL fluids from rabbits ventilated with an injurious ventilatory regimen. These alarmins stimulate lung cells to produce bioactive IL-­‐1, and are likely to represent the proximal endogenous mediators of VILI and ARDS, released by injured pulmonary cells.