Correspondence

Biotrauma Hypothesis of Ventilator-induced Lung Injury

To the Editor:

In a new perspective, Dreyfuss and colleagues (1) question the existence and part of cytokines during ventilator-induced lung injury (VILI), in agreement with their merely published work in the field of mediators and biotrauma, in which they failed to confirm a certain quantity of of our findings (see regard 25 in Dreyfuss and colleagues). Our criticism of their perspective is not solely that it focused on many trivial so-called inconsistencies within and between studies, further that it did so without a conceptual framework. Provision for the following three conceptions would have clarified many misconceptions.

First, Dreyfuss and colleagues (1) do not systematically distinguish between the sum of two units independent parts of the biotrauma hypothesis: (1) that ventilation may cause release of mediators, and (2) that these mediators have biological actions. Because the biotrauma hypothesis is rather recent until now most work has been relate toed with the first part of this hypothesis and ample evidence (the 2003 American Thoracic Society International conversation was abound in such studies) exists to support that ventilation or elongate can activate cells and stir up mediator release. Differences among studies or nonzero baseline plains in control subjects do not invalidate this general notion, and the question at issue now is not whether, however how ventilation causes mediator release. The arguably more important question transactions the biological role of these mediators. This vexed question has only recently begun to be addressed, and to this time there are already at least three studies in healthy animals where ventilation-induced lung injury was apparently not caused directly by dint of the mechanical forces themselves, nevertheless by the mediators produced in replication to these forces (2, 3 respect 50 in Dreyfuss and colleagues). united of these studies, showing the pivotal part of macrophage inflammatory protein (MIP)-2[alpha] receptors (CXCR2) in a murine VILI pattern (Reference 50 in Dreyfuss and colleagues) is dismissed by means of Dreyfuss and colleagues (1) with the statement: "It is not remarkably surprising that injured lungs eventually recruit neutrophils." The critical point is that neutrophils were recruited to the lung before injury, as demonstrated by way of the prevention of lung injury when neutrophil sequestration was shapeed This is exactly what the biotrauma hypothesis would predict.

Second the assessment that this is "not surprising" is based in succession the second conceptual deficit of this review, namely that it does not systematically distinguish between one-hit and two-hit designs Almost all of the work before 1996 used two-hit archetypes typically the lung lavage gauge followed by different ventilation strategies. Increased cytokine on a levels caused by injurious ventilatory strategies have been observ in a number of two-hit patterns but the interaction between the first (eg lavage or acid aspiration) and the secondary hit (ventilation) is very complicated and the initial stimulus for mediator release and leukocyte activation is difficult to define. Therefore, investigators have started to investigate the general intents of ventilation in healthy lung (one-hit model) And whereas in the one-hit prototypes it has been difficult to always find out tumor necrosis factor (TNF; which is overemphasized according to Dreyfuss and colleagues), many other mediators were not rarely found such as interleukin (IL)-6, MIP-2[alpha], MIP-1[alpha], and sometimes equable TNF (3, 4, Reference 50 in Dreyfuss and colleagues).

Third, ventilation can cause mediator release at at least four fundamentally different mechanisms: necrosis, decompartmentalization, make tense or shear stress (5). Unfortunately, Dreyfuss and colleagues (1) confuse these mechanisms. For instance, they mistake the standard of ventilation-induced mediator release in uninjured perfused mouse lung (Reference 24 and 30 in Dreyfuss and colleagues) for a original of mediator release caused through decompartmentalization (see p. 1,468 in intimation 1). The difference between as well-as; not only-but also; not only-but; not alone-but models is illustrated by the antithetic efficiencys of surfactant: In the perfused mouse lung pattern where lung integrity is maintained, surfactant treatment (most likely because it improves stretch) augments mediator release (6); whereas in a pattern of decompartmentalization surfactant has the opposite validity and reduces mediator release (7) The notion that mediator horizontals can increase in response to ventilation-induced solitary abode; squalid necrosis and decompartmentalization does not hinder the possibility that under les injurious ventilation strategies, stretching of the lung can activate specific mechanotransduction pathways (5)

Thus, principally of the so-called inconsistencies could have been reconciled by the agency of systematic application of a conceptual framework. In addition, many other arguments in this perspective appear to be misconstrued. For instance, the critique of the work of Stuber and colleagues (Reference 60 in Dreyfuss and colleagues) reads, "It is also difficult to understand on what account changes in concentration occurred in such a manner rapidly . . .," thus suggesting-without any further argumentation-that there is something unfit with the data. This sort of argument should not be used in a scientific paper-it betrays the authors' biases. We also fail to behold why Dreyfuss and colleagues believe that the additive tenor between stretch and lipopolysaccharide (LPS) in the work of Tremblay and colleagues (Reference 23 in Dreyfuss and colleagues) is difficult to explain, and calm if so, what this would prove? common possible explanation is that the pair phenomena act via a everyday mechanism (e.g., via NF-[kappa]B) that becomes saturated at high plains of activation. Furthermore, in contrast to what is insinuated, mediator release in rejoinder to overventilation cannot be explained at LPS contamination, because it also come to one's minds in LPS-resistant animals (Reference 30 in Dreyfuss and colleagues). Another putative discrepancy is that an IL-1 receptor antagonist was partially protective, whereas there was no significant increase in IL-1 evens (Reference 43 in Dreyfuss and colleagues). Possible explanations for this finding that are not mentioned include incorrect liming of the IL-1 measurement and the well known fact that the of the same height of cytokines that can be measured in vivo may no other than represent the tip of the iceberg (8) In of the like kind cases, studies with antagonists can be earnestly more revealing. Undoubtedly, the biology of mediators and their weights is complex - important factors (among many) to consider are the puissance of the stimulus, the injury design and the lime course. Simply stating that there are "discrepancies" among studies without dissecting abroad these possibilities is insufficient.