Basic Science in Ventilator-induced Lung Injury
Implications for the Bedside

Arthur S. Slutsky

St. Michael's Hospital, University of Toronto, Toronto, Canada

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Over the past two decades we have realized that mechanical ventilation, the life sustaining therapy that has saved thousands of lives since the polio epidemic, can exacerbate or even cause lung injury. Over the past few years, we have begun to unravel the mechanisms underlying the detrimental effects of mechanical ventilation, and have obtained strong clinical data indicating the importance of iatrogenic lung injury (1). The current study from Held and colleagues, reported in this issue of the Journal (2) (pp. 711-716), significantly advances our understanding of the signal transduction mechanisms involved in one mechanism of injury: the release of mediators due to different ventilatory strategies, so-called biotrauma (3, 4). The study is important because it helps illuminate the mechanotransduction mechanisms, and in so doing suggests novel therapeutic targets to abrogate the mediator release due to mechanical ventilation.

The study by Held and colleagues helps elucidate the signal transduction mechanisms in a number of ways. First, it confirms previous studies that have demonstrated that the signaling cascade operates via an NF-B pathway that translates the ventilatory (physical) stimulus into a chemical (mediator) response (5). NF-B is a protein transcription factor that enhances transcription of a number of genes, most notably cytokines. Second, it confirms the steroid responsiveness of this release of cytokines (5), a finding that has obvious potential clinical application. Third, and most important, this study demonstrates that although the signal transduction mechanisms responsible for biotrauma act, at least partly, via NF-B (similar to lipopolysaccharide [LPS] signaling), the upstream mechanisms appear to be different. As shown by a number of groups, LPS signaling acts via a Toll-like receptor (TLR) (6). The Toll gene, originally identified in Drosophila melanogaster, encodes a receptor that can bind to surface epitopes/ligands on bacteria to effect signaling to the nucleus from the cell membrane. In humans, there are at least 10 types of TLR; one of these, TLR4, appears to be relatively specific for LPS whereas TLR2 mediates responses to gram-positive organisms. The most convincing data in support of the importance of TLR4 in LPS signaling are provided by experiments in C3H/HeJ mice (7), which have been known for more than 20 years to be endotoxin insensitive. In C3H/HeJ mice, LPS does not cause translocation of NF-B and does not cause an increase in inflammatory cytokines; this defective signaling has been shown to be due to a mutation in the TLR4-encoding gene (7). In the present study, Held and colleagues made use of C3H/HeJ mice to demonstrate that the mediator release due to overstretch of the lung occurs in these mice via translocation of NF-B, despite the fact that there is no release of cytokines in response to LPS alone, thus demonstrating that the upstream events for signaling by LPS are different from those that initiate biotrauma.

Why is this result so exciting? This finding suggests the possibility that it will be possible to treat and/or prevent biotrauma without necessarily affecting other relevant host defense mechanisms. Held and others have shown that corticosteroids can attenuate release of mediators due to lung stretch (2, 5). However, steroids represent a sledgehammer approach to the problem and block many pathways we don't want blocked; clinically, this is manifested as an increased risk of infection in patients treated with corticosteroids. The findings of the current study suggest an approach to circumvent this problem. If we think of the LPS signaling pathway as a major pathway for innate immunity, it may be possible to target the biotrauma signaling pathway without affecting the innate immunity pathway. If this is correct, then one could potentially limit biotrauma by targeting specific signal transduction pathways proximal to NF-B that are important in ventilation-induced release of mediators, but that play no role in LPS signaling. In this way, the basic findings of Held and colleagues could have tremendous implications at the bedside.

But why should this anticytokine approach be effective when most anticytokine trials have been ineffective in the context of sepsis? First, most sepsis trials have blocked a single cytokine, despite the fact that there are multiple cytokines and multiple pathways. Blocking the biotrauma pathway proximal to NF-B would block the signal transduction pathway relatively proximally, and hence would theoretically affect multiple cytokines. Second, most anticytokine therapies are effective in animal models when given before the septic insult; this is impossible to do in most cases of sepsis because the diagnosis is made by recognition of signs, symptoms, and laboratory data related to the host's response to the stimulus, implying that therapy can only begin after the initiating stimulus. Biotrauma associated with ventilator-induced lung injury is noteworthy in that we know exactly when the stimulus will begin (when mechanical ventilation is initiated), and more importantly, we can thus begin therapy before initiation of this insult. A number of studies of different animal models suggest that this approach may have merit (8, 9).

Furthermore, future studies that more specifically elucidate a specific patient's susceptibility to biotrauma, perhaps on the basis of the signal transduction pathways, may suggest which patients are more likely to benefit from antimediator therapy. There are now a number of studies that have demonstrated that a patient's genetic make-up may predict his/her response to sepsis (10). Specifically, septic patients who are homozygous for a specific polymorphism in the tumor necrosis factor  (TNF-) gene have an increased risk of death, presumably because of increased TNF- levels. Another example of genetic susceptibility was recently provided by Arbour and colleagues, who demonstrated that differences in responsiveness to inhaled LPS in humans may be due to differences in common mutations in TLR4 (11). If similar types of polymorphisms are important in the context of biotrauma, then intensivists in the future may decide whether to use antimediator therapy in a ventilated patient on the basis of the patient's particular genotype profile. Within the context of this model, patients who are genetically susceptible to biotrauma would be the ones who receive this therapy (12). Basic studies, such as the present one by Held and colleagues, are critical if approaches such as this are to become a reality in the intensive care unit of the future.

	References

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