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M ECHANICAL ventilation (MV) is frequently mandatory in patients with respiratory failure. However, MV has the potential to induce respiratory muscle dysfunction, and diaphragm weakness is associated with a prolonged need for MV. Human studies confirm results from animal studies showing that inactivity of respiratory muscles with controlled MV leads to structural injury and atrophy of diaphragmatic fibers. The exact upstream mechanisms that initiate muscle injury and fiber atrophy are unclear. In this month’s issue of ANESTHESIOLOGY, Schellekens et al. present the results of an animal study that tested the role of Toll-like receptor 4 (TLR4) in the development of ventilator-induced diaphragm atrophy. In their experiments, wild-type and TLR4 knockout mice were ventilated for 8 h. Controlled MV in wild-type mice resulted in a reduction of the diaphragm myosin heavy chain content by approximately 50% as compared with spontaneously breathing mice, which was associated with increased local concentrations of the inflammatory mediators interleukin-6 and keratinocyte-derived chemokine, the mouse analog of human interleukin-8. In TLR4 knockout mice, MV neither affected myosin content nor diaphragm interleukin-6 and keratinocyte-derived chemokine levels. Muscle fiber atrophy can be a consequence of decreased protein synthesis as well as increased proteolysis. The former was demonstrated in a rat model in which 6 h of controlled MV decreased the synthesis of diaphragmatic mixed muscle protein (i.e., an average synthesis rate for all muscle proteins) and myosin heavy chain protein because of impairment of posttranscriptional events. Four proteolysis pathways have also been reported to play a role in ventilator-induced diaphragm atrophy. Animal and human studies demonstrate up-regulation of 1) the calpain (calcium-dependent proteases) and 2) caspase-3 pathways, both important for the initial step of sarcomeric protein degradation, and 3) the ubiquitin-proteasome pathway, central for further processing of partially cleaved and disassembled myofilament proteins. A more recent human study revealed up-regulation of the 4) autophagy pathway during MV. Autophagy, which literally means self-eating, is characterized by the degradation of cytoplasmic organelles and proteins in phagolysosomes. This pathway is important for cell survival by recycling old organelles and proteins during normal homeostasis, but can be quickly upregulated when increased energy is needed. In Schellekens et al.’s analysis of activation of the caspase-3, ubiquitin-proteasome, and autophagy pathways, the latter was found associated with TLR4 mediated ventilator-induced diaphragm atrophy. TLRs are important pattern recognition receptors crucial for the detection of invading pathogens. TLR4, for example, recognizes lipopolysaccharide present in the outer membrane of Gram-negative bacteria. In the last decade it became clear that TLRs are also activated by endogenous danger signals. These so-called damage-associated molecular patterns are molecules released from injured tissue that also initiate an innate immune response. Therefore, TLR4 activation is not only important during infections but can also play a central role during sterile inflammation. Schellekens et al. suggest TLR4 to be important in the pathogenesis of ventilatorinduced diaphragm atrophy, but how? A previous animal study demonstrated ventilator-induced lung inflammation to be dependent on TLR4 activation. Interestingly, endogenous TLR4 agonists were found in bronchoalveolar lavage fluid. Schellekens et al. hypothesize that these endogenous TLR4 ligands might be responsible for activation of TLR4 in ventilator-induced diaphragm atrophy. But how can these damage-associated molecular patterns reach the diaphragm? Are these ligands also present in plasma? Does the injured diaphragm itself release damage-

Do We Need to Pay Toll on the Bridge from Innate Immunity to Ventilator-induced Diaphragm Atrophy?