Cytokines during ventilator-induced lung injury: a word of caution.

The clinical relevance of experimental ventilatorinduced lung injury (VILI) (1) has recently received a resounding illustration by the Acute Respiratory Distress Syndrome (ARDS) Network trial that showed a 22% reduction of mortality in patients suffering from ARDS when lung mechanical stress was lessened by tidal volume reduction during mechanical ventilation (2). This clinical confirmation of the concept of VILI has also undisputedly substantiated experimental findings that suggest that excessive tidal volume and/or end-inspiratory lung volume is the main determinant of VILI. However, the precise mechanisms by which excessive lung volume leads to alveolar damage remains to be elucidated. Mechanical stress may generate lesions because the resistance of the alveolar-capillary barrier is not infinite. Indeed, Mead and Takishima (3) had calculated that a fully expanded lung surrounding an atelectatic region would be stretched by approximately 140 cm H2O when the transpulmonary pressure is 30 cm H2O. Such high pressures may obviously result in cell distortion and rupture (4,5). The possibility that inflammatory cells and mediators (such as proinflammatory cytokines) contribute to the genesis of VILI has been investigated (6–10). In one of the earliest studies on this subject, Woo and Hedley-White (6) observed that overinflation produced edema in open-chest dogs, and that leukocytes accumulated in the vasculature and macrophages in the alveoli. Further studies have confirmed these results (11) and shown that high transpulmonary pressure increased the transit time of leukocytes in the lungs of rabbits (12). Conversely, when animals are depleted in neutrophils, highvolume pulmonary edema is less severe than in nondepleted animals (13). Recruitment and activation of neutrophils and macrophages are compulsory steps to the lung inflammatory response. Adhesion molecules, such as ICAM-1 and Mac1, play an important role in this phenomenon. Their implication in VILI had not yet been investigated. In the February 2001 issue of Anesthesia & Analgesia, Imanaka et al. (14) elegantly studied the expression of such adhesion molecules during experimental VILI. Ventilating rats for 40 min with 45 cm H2O peak inspiratory pressure resulted in a significant upregulation of Mac1 and ICAM-1 on alveolar macrophages in comparison with alveolar macrophages retrieved from animals ventilated for the same duration with 7 cm H2O peak inspiratory pressure. Upregulation of Mac-1 on neutrophils retrieved from animals ventilated with high peak inspiratory pressure tended to be greater than with low peak inspiratory pressure. These authors were also interested in the expression of a profibrogenetic factor, transforming growth factor (TGF)-b1. At the mRNA level, they found that levels of TGF-b1 were increased in the lungs of animals ventilated with the high peak inspiratory pressure. Despite the occurrence of severe pulmonary edema in these animals (45 cm H2O peak inspiratory pressure), the authors found no increase in levels of mRNA for tumor necrosis factor (TNF)-a (14). Although they did not measure TNF-a at the protein level, their findings are in total agreement with several other in vivo studies clearly suggesting that mechanical ventilation per se does not induce the release of TNF-a into airspaces (15,16). Verbrugge et al. (15) showed that intact rats mechanically ventilated with 32 cm H2O peak inspiratory pressure released no TNF-a into airspaces despite the occurrence of severe pulmonary edema (15). Consistent findings were obtained in vivo in intact rats in which no TNF-a was found in the bronchoalveolar lavage (BAL) fluid after 2 h of injurious mechanical ventilation (42 mL/kg tidal volume) (16). Using an in vitro model of mechanical stretch, Pugin et al. (17) demonstrated that human alveolar macrophages released no TNF-a when submitted to cyclic pressurestretching strain (mimicking alveolar distention) that induced the release of interleukin (IL)-8. Using a similar approach, Vlahakis et al. (18) obtained consistent Accepted for publication April 16, 2001. Address correspondence and reprint requests to Didier Dreyfuss, MD, Service de Réanimation Médicale, Hôpital Louis Mourier, 178 rue des Renouillers, 92700 Colombes, France. Address e-mail to didier.dreyfuss@lmr.ap-hop-paris.fr.