Affiliations: Rochester, NY
Dr. Papadakos is Associate Professor, Anesthesiology and Surgery, University of Rochester, Department of Anesthesiology, and Professor, Respiratory Care, State University of New York at Genesee Community College.
Correspondence to: Peter J. Papadakos, MD, FCCP, University of Rochester, Department of Anesthesiology, 601 Elmwood Ave, Rochester, NY 14642; e-mail: firstname.lastname@example.org
The leading cause of death in patients with ARDS is multiorgan failure (MOF) caused by a systemic inflammatory response. This finding has led to a great evolution in our understanding of ARDS since it was first reported in 1967.1 We have struggled over the last number of years to find the molecular basis for the changes we see in the gross pathology of the lung and other end organs.
Many investigators have begun to develop the relationship between cytokine modulation and cytokine levels in the physiology of ARDS and how this syndrome relates to the systemic inflammatory response and end-organ dysfunction. Donnelly and colleagues2found that patients at risk for ARDS who had higher levels of interleukin (IL)-8 in BAL fluid subsequently progressed to ARDS, thus providing a potential early marker for the development of this syndrome and some clues as to pathogenesis. The clinical importance of this developing understanding of cytokine modulation has led to studies looking at how the simplest treatment for respiratory failure and ARDS, mechanical ventilation, contributes to MOF through the spread of inflammatory mediators.3–4
In this issue of CHEST (see page 1716), Takatsuka et al report how certain patients who are positive for human leukocyte antigen (HLA)-B51 or B-52 respond to the administration of granulocyte colony- stimulating factor (G-CSF). These patients showed significant increases in tumor necrosis factor (TNF)-α and IL-8 at the onset of ARDS. This data differed from a large group of patients who received G-CSF and did not have respiratory dysfunction develop, but had neither HLA-B51 or B52 antigens. It points out that some groups of patients may be genetically primed to have a multiplied response develop to a trigger, and thus release increased levels of cytokines than other patients.
Work from Moine et al5showed that patients with ARDS had increased activation of the transcriptional regulatory factor nuclear factor-κB in alveolar macrophages. This work suggests a transcriptional mechanism that may be important in maintaining the persistently elevated expression of proinflammatory cytokines and other mediators that characterize ARDS. Regional alterations of proinflammatory and immunoregulatory cytokine gene expression appear, therefore, to greatly contribute to the patient’s response to a trigger and maintenance of response in patients with established ARDS. Persistently elevated levels of cytokines, including TNF-α and IL-8 in BAL, have been correlated with poor outcome.6The patients in this current study showed an elevation of both of these cytokines. We know that a primary trigger for the inflammatory response in circulation is the adhesion of neutrophils to vascular endothelial cells and their migration and infiltration into stroma, and this mechanism plays a basic role in the pathogenesis of ARDS. Both TNF-α and IL-8 are key to this response.7
We must continue to develop the genetic map of patients at risk of having ARDS and systemic inflammatory response develop. In understanding the gene, we may better understand and treat ARDS. Gene therapy represents one of several new technologies that are changing the face of medicine and medical technology. Molecular biology, in general, has greatly advanced our understanding of the pathogenesis of many diseases; gene therapy is poised to implement that new knowledge.
Clinical trials are now under way with a variety of gene therapy approaches for the inherited diseases, but as this research has gone forward, it has become clear that even acquired diseases have a genetic component, which theoretically could be a target for gene therapy.8 Therefore, our understanding of specific patients at risk may lead to new molecular-based treatments for ARDS. By changing gene expression, we may prevent the elevation of certain inflammatory cytokines, and the reaction of the body to these cytokines.
The article by Takatsuka et al in this issue of CHEST only supports the importance in the interrelationship of both clinical and basic science research and how this work will lead us down the uncharted path of the molecular basis of inflammatory diseases. We must collect data on the genetic makeup of patients with severe ARDS and how these patients are different or similar to patients who do not develop ARDS. This may contribute more to patient care than novel new therapies targeted at only one or more cytokines.
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