Pathogenesis of ventilator-induced lung injury: trials and tribulations

Lorraine N. Tremblay, Arthur S. Slutsky
2005 American Journal of Physiology - Lung cellular and Molecular Physiology  
RESEARCH INTO VENTILATOR-INDUCED LUNG INJURY (VILI) spans the decades since this life-sustaining technology was introduced into widespread clinical use in the mid-twentieth century (24). Early on, it was recognized that lungs ventilated with high ventilatory pressures have a propensity to develop air leaks (barotrauma). However, investigators soon realized that it was excessive lung volume (volutrauma) rather than the ventilatory airway pressure per se that produced lung injury (8). At the
more » ... end of the spectrum, ventilation using low end-expiratory lung volumes that allowed repetitive alveolar opening and collapse was also injurious (atelectrauma) (34). Over the past few years there has been a realization that injury due to mechanical ventilation represents not only structural disruption of the lung but can also have an inflammatory component associated with mediator release (biotrauma), which can worsen lung injury and potentially cause systemic organ dysfunction (25, 27, 35, 41) . One of the earliest studies to suggest an inflammatory mechanism for VILI was that of Kawano et al. (14). Having noticed an association between the development of VILI and the presence of increased numbers of neutrophils within surfactant-depleted lungs, they repeated experiments in neutrophil-depleted rabbits and found only minimal lung injury. Numerous studies followed exploring the role of various inflammatory mediators in a variety of live animal and ex vivo models. In the hunt for a key putative mediator, it was not surprising that TNF-␣, one of the first cytokines to be characterized and a pivotal mediator of the inflammatory cascade, received a great deal of attention. These early studies, however, produced a debate as to the role of TNF-␣ in VILI (31, 42, 46) . In the presence of a preexisting stimulus such as LPS or surfactant depletion, lungs subjected to injurious mechanical ventilation often had elevated levels of lung TNF-␣ detected (13, 15, 17-19, 29, 31, 37-39), but not always (43). Similarly, in lungs injured purely by mechanical ventilation, elevated TNF-␣ levels were detected in many studies (3, 4, 6, 20, 26, 30, 32, 36, 39, 40, 45, 46) , but not all (11, 31). Were these conflicting results due to inherent differences in the studies (e.g., different species/ strains, in vivo vs. ex vivo models, different time points, varying severity in lung injury, contamination by endotoxin) or problems with the assays (e.g., mRNA vs. protein, different reagents/sensitivities, sample degradation by endogenous proteases, presence of inhibitors)? And, perhaps more importantly, what role (if any) were the inflammatory mediators such as TNF-␣ playing in the pathogenesis of VILI and systemic injury? The report from Wilson et al., one of the current articles in focus (Ref. 46, see p. L599 in this issue), presents a novel approach using transgenic mice to further elucidate the role of TNF-␣ in ventilator-induced lung inflammation. This study builds on the results of two earlier studies in which Wilson and colleagues used a mouse model and demonstrated that 1) high-volume ventilation produces an early but transient increase in bronchoalveolar lavage TNF-␣ (as detected by ELISA and bioactivity) (45); and 2) high-volume ventilation produces early changes in deformability of circulating polymorphonuclear leukocytes (PMN) and increases PMN sequestration mediated by L-selectin within the pulmonary vasculature (5, 45). In their latest study, Wilson et al. (46) examined the effect of high-volume ventilation on the lung inflammatory response (as assessed by lung neutrophil infiltration) in either wild-type mice or double knockout (DKO) mice lacking TNF receptors (46). They also examined the effect on neutrophil infiltration of administering anti-TNF-␣ antibody, either intravenously or intratracheally. The three salient findings were 1) in the absence of functional TNF-␣ signaling (DKO mice or intra-alveolar anti-TNF-␣ antibody), neutrophil influx into lungs of mice subjected to an injurious ventilation strategy was significantly reduced; 2) reduced neutrophil infiltration occurred despite no reduction in alveolar CXC chemokines [macrophage inflammatory protein-2 (MIP-2) or keratinocyte-derived chemokine]; and 3) in contrast to intratracheal anti-TNF-␣ antibody, intravenous anti-TNF-␣ antibody had no apparent effect on PMN influx into the lungs. As such, Wilson et al. concluded that TNF-␣ signaling mediates, in part, the pulmonary inflammation induced by high-stretch ventilation in mice (46). Will this study definitively lay to rest the debate about the role of TNF-␣ in the pathogenesis of VILI? No, particularly if this study is looked at in isolation. As the authors clearly point out, the end point of the current study was inflammation (not injury) as assessed by neutrophils in lung lavage at the end of a 4-h ventilation protocol, and the mere presence of increased neutrophils is not synonymous with subsequent lung injury (16). Furthermore, as the authors concede, there are model-and species-specific limitations that prevent direct extrapolation of their findings to other species (1). However, if viewed in the context of the literature, the study by Wilson et al. (46) does identify a novel role for TNF-␣ signaling in mediating highvolume, ventilation-induced neutrophil lung infiltration in mice, and it further strengthens the argument that the release of inflammatory mediators with injurious ventilation is an early event that precedes neutrophil infiltration and the development of histological signs of lung injury. Indeed, a couple of previous studies have demonstrated that the use of antibodies to TNF-␣ decreased VILI or its systemic sequelae. For example, Imai and colleagues (13) demonstrated that administration of intratracheal anti-TNF-␣ antibody in an in vivo surfactant-Address for reprint requests and other correspondence: A. S. Slutsky, St. Michael's Hospital, 30 Bond St., Rm. 4-042,
doi:10.1152/ajplung.00438.2004 pmid:15757952 fatcat:2dk62kyijvcx3pvd3bkjr7yfxm