Rationale:Mechanical ventilation is associated with diaphragm dysfunction and systemic inflammation. Whether inflammation is involved in ventilator−induced diaphragm dysfunction is largely unknown. Activation of toll like receptor−4 (TLR−4) activates intracellular inflammatory cascades. Aim: To investigate the role of toll like receptor 4 (TLR−4) signaling in the development of ventilator−induced diaphragm dysfunction. Methods: Wild type (WT, n = 4) and TLR−4 knock−out (TLR4−KO, n = 4) mice were mechanically ventilated for 8 hours (tidal volume 8 ml/kg; PEEP 1,5 cm H20; respiratory rate 170/min). Immediately after sacrifice diaphragm muscle bundles were dissected. From these bundles chemically skinned diaphragm fibers were isolated. Absolute maximal force generation was determined upon calcium activation (pCa 4.5). Results: Pao2 / Fio2 ratio were not significantly different between WT and TLR4−KO mice after 8 hours of mechanical ventilation (492 ± 40 and 531 ± 45 respectively). Absolute maximal force generation of diaphragm fibers from TLR4 KO mice was 15% higher compared to WT mice (2,34 ± 0.32 mg vs. 2,04 ± 0.13 mg respectively).
Conclusion:The present study demonstrates that TLR−4 signaling is involved in the development of ventilator−induced diaphragm dysfunction. TLR−4 signaling did not affect pulmonary function in mechanically ventilated mice. This abstract is funded by: None. Am J Respir Crit Care Med 179;2009:A4196 Internet address: www.atsjournals.org Online Abstracts Issue
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