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41st Aspen Lung Conference: Overview
CHEST VOLUME 116 / NUMBER 1 / JULY, 1999 SUPPLEMENT
Introduction: Acute Lung Injury (CHEST 1999; 116:1S) cute lung injury was the focus of the 41st Annual Thomas L. Petty Aspen Lung Conference. ARDS and acute lung injury had also been the topic 5 years previously and initially, in organizing the conference, we were concerned that there was not sufficient evolution in the field to justify a return to the same subject within such a short interval. Our concerns were rapidly laid to rest as we generated our first list of topics that we hoped could be covered. Our enthusiasm for a review of advances in acute lung injury grew as the conference took form. We believe that our enthusiasm for the topics covered was shared by the participants in the meeting and will be shared by readers of the summaries of the presentations. We were extremely fortunate to have Tom Petty, MD, Master FCCP, as the initial speaker for the conference. He provided an enlightening historical perspective of ARDS that served as an outstanding introduction for the state-of-the-art and scientific presentations. The Aspen setting provides ample opportunity for interaction between speakers and the audience. This conference was not an exception to this, and discussions concerning mechanisms and manifestations of acute lung injury started at breakfast and continued into the evening. Michael Matthay, MD, FCCP, who provided an outstanding summary of the meeting, was able to achieve the seemingly impossible task of providing a context for the rich scientific material presented. We are deeply indebted to all of the conference participants who helped make this meeting a success. The conference was centered on the intracellular and extracellular signaling mechanisms leading to inflammatory injury in the lungs. We came away with an enhanced appreciation of the multiplicity of pathways that can lead to lung injury. The future challenge will be in developing useful therapies for patients with ARDS and acute lung injury based on our increased understanding of the mechanisms leading to these clinical entities. Jeanne Cleary deserves special recognition for her contribution to the conference organization. She was able to keep us to a time schedule in developing the conference and attended to the myriad of details,
A
Correspondence to: Edward Abraham, MD, FCCP, Pulmonary Science, Critical Care, Univ Colorado Health Science Center, 4200 E Ninth Ave, Denver, CO 80262
including hotels and catering, required for the success of the meeting. We would like to thank Marvin Schwarz, MD, FCCP, for his continuing devotion to the Aspen conference series. Mike Baird and Wayne Silvers again provided essential background help. As always, the conference would not have been possible without the continued support of the Francis Families Foundation and the many representatives of the pharmaceutical industry. Edward Abraham, MD, FCCP, Chair Lance Terada, MD, Co-Chair University of Colorado Health Science Center Denver, CO
41st Aspen Lung Conference: Overview* Thomas L. Petty, MD, Master FCCP
(CHEST 1999; 116:1S–2S) variety of catastrophic events have been known to lead to acute lung injury since World War I. Early terms for acute lung injury were “shock lung,” “postperfusion lung,” “traumatic wet lung,” and “congestive atelectasis.” These massive lung injury states were described only following autopsies. In the mid 1960s, the Denver group recognized a common denominator in patients who had suffered shock, trauma, overwhelming infections, and miscellaneous other conditions that resulted in the dramatic onset of acute respiratory distress, refractory hypoxemia, bilateral symmetric pulmonary infiltrates, and reduced lung compliance. Five of 12 patients survived with the application of mechanical ventilation and the use of positive end-expiratory pressure. This clinical state was first described as “acute respiratory distress in adults” and later as ARDS.1,2 The “adult designation,” however, was inappropriate, since the youngest patient in our original series was 11 years old, and the next oldest was 15 years old. The mean age was 29.4 years. In our original description of ARDS, we recognized surfactant defects in the two autopsy specimens studied
A
*From Presbyterian/St. Luke’s Hospital, Denver, CO. Correspondence to: Thomas L. Petty, MD, Master FCCP, University of Colorado Health Science Center, 1850 High St, Denver, CO 80218 CHEST / 116 / 1 / JULY, 1999 SUPPLEMENT
1S
and the presence of destructive proteolytic enzymes. In observing ARDS for . 30 years, a huge amount of basic science has identified a myriad of cellular and humoral mediators in acute lung injury, with a panoply of inflammatory cytokines and chemokines, while enhancing and inhibiting mediators of inflammation. Supportive care of patients during the past third of a century has improved to the point that . 50% can survive.3 Thus far, clinical trials investigating the efficacy and safety of new pharmaceuticals aimed at blocking the inflammatory mediators of disease have not proved successful.4 The development of an ARDS clinical trials consortium offers the machinery to test additional new therapeutic agents.5 Although it is doubtful that a single “silver bullet” will stop the cascade of events resulting in ARDS, it is possible that the replacement of surfactant in early stages or a combination of mediator blockers might alter the outcome of the basic biological processes resulting in ARDS. The first Aspen Lung Conference on ARDS was the 16th, in 1973.6,7 The second was in 1993.8 Now, 25 years later, the 41st Aspen Lung Conference has enlightened us further about the basic nature of ARDS. Future progress depends on the clinical application of new therapeutic agents aimed at the basic biological processes associated with ARDS. An imaginative approach to therapy is needed in the future.
References 1 Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967; 2:319 –323 2 Petty TL, Ashbaugh DG. The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management. Chest 1971; 60:233–239 3 Milberg JA, Davis DR, Steinberg KP, et al. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 1995; 273:306 –309 4 Levy PC, Utell MJ, Sickel JZ, et al. The acute respiratory distress syndrome: current trends in pathogenesis and management. Compr Ther 1995; 21:438 – 444 5 Bernard GR, Artigas A, Brigham KL, et al. The AmericanEuropean Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818 – 824 6 Petty TL, Hudson LD, Ashbaugh DG. The 16th Aspen Lung Conference. Chest 1974; 65(Suppl;part 1):1S– 67S 7 Petty TL, Hudson LD, Ashbaugh DG. The 16th Aspen Lung Conference. Chest 1974; 65(Suppl;part 2):1S– 46S 8 Petty TL. The acute respiratory distress syndrome: historical perspective. Chest 1994; 105(Suppl):44S– 47S
Lung Cytokines and ARDS* Roger S. Mitchell Lecture Thomas R. Martin, MD, FCCP
(CHEST 1999; 116:2S– 8S) 2S
cellular and molecular basis for ARDS remains T heuncertain . 30 years after the original description of the syndrome. With the explosion of information about the involvement of cells and cytokines in inflammation, there has been intense interest in understanding the involvement of cytokines in the pathogenesis of ARDS. Cytokines are low-molecular-weight soluble proteins (generally , 30 kda) that transmit signals between cells. It is now clear that cytokine production is not limited to lymphoid and myeloid cells, and that cytokines produced by epithelial and mesenchymal cells amplify inflammatory responses in the lungs and other organs. Cytokines are produced in “cascades” in which the initial cytokine signals are amplified many-fold by target cells, such as epithelial cells, fibroblasts, and endothelial cells. Cytokines function in “networks” in which feedback occurs at many points to coordinate and regulate cytokine and cellular responses. There are three major reasons to study the involvement of cytokines in patients with ARDS: first, to understand the pathogenesis of the disease; second, to identify markers that might be used to determine which patients are at highest risk for developing ARDS; and third, to identify markers that can predict outcome, including survival and/or long-term disability.1 Studies of single cytokines have shown that no single cytokine consistently predicts either the onset or the outcome of ARDS, despite promising early results. Instead, it is now recognized that a balance of proinflammatory and anti-inflammatory factors influences the net inflammatory response in the lungs.2 Current efforts are directed at defining the cytokine balance that exists in the lungs at the onset of ARDS, and how this balance changes over time.
Sampling and Measurement Considerations The study of cytokine balance in the lungs is difficult because of sampling and measurement issues. Experimental studies suggest that cytokine responses normally are compartmentalized in the lungs, and that the study of blood specimens provides an incomplete reflection of inflammatory events in the lungs.3 However, compartmentalization is lost to some extent during severe inflammatory responses.4 Thus, measurements of cytokines in the lungs are likely to be more valuable than measurements in plasma or serum. Sampling cytokines in the lungs is difficult, because cytokines function not only in the alveolar compartment, where they may exist as soluble constituents of alveolar fluids, but also in the tissue compartment, where they bind to components of the extracellular matrix. Thus, sampling alveolar fluids by direct aspiration of the distal airways or by BAL may provide incomplete information about the concentration and function of spe*From the Medical Research Service, Seattle VA Medical Center, and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA. Supported in part by grants HL30542, A129103, and GM37696 from the National Institutes of Health, and the Medical Research Service of the Department of Veterans Affairs. Correspondence to: Thomas R. Martin, MD, FCCP, Pulmonary Research Labs, 151L, Seattle VA Medical Center, 1660 S Columbian Way, Seattle, WA 98108; e-mail: [email protected] Thomas L. Petty 41st Annual Aspen Lung Conference: Acute Lung Injury
Introduction: Acute Lung Injury (CHEST 1999; 116:1S) cute lung injury was the focus of the 41st Annual Thomas L. Petty Aspen Lung Conference. ARDS and acute lung injury had also been the topic 5 years previously and initially, in organizing the conference, we were concerned that there was not sufficient evolution in the field to justify a return to the same subject within such a short interval. Our concerns were rapidly laid to rest as we generated our first list of topics that we hoped could be covered. Our enthusiasm for a review of advances in acute lung injury grew as the conference took form. We believe that our enthusiasm for the topics covered was shared by the participants in the meeting and will be shared by readers of the summaries of the presentations. We were extremely fortunate to have Tom Petty, MD, Master FCCP, as the initial speaker for the conference. He provided an enlightening historical perspective of ARDS that served as an outstanding introduction for the state-of-the-art and scientific presentations. The Aspen setting provides ample opportunity for interaction between speakers and the audience. This conference was not an exception to this, and discussions concerning mechanisms and manifestations of acute lung injury started at breakfast and continued into the evening. Michael Matthay, MD, FCCP, who provided an outstanding summary of the meeting, was able to achieve the seemingly impossible task of providing a context for the rich scientific material presented. We are deeply indebted to all of the conference participants who helped make this meeting a success. The conference was centered on the intracellular and extracellular signaling mechanisms leading to inflammatory injury in the lungs. We came away with an enhanced appreciation of the multiplicity of pathways that can lead to lung injury. The future challenge will be in developing useful therapies for patients with ARDS and acute lung injury based on our increased understanding of the mechanisms leading to these clinical entities. Jeanne Cleary deserves special recognition for her contribution to the conference organization. She was able to keep us to a time schedule in developing the conference and attended to the myriad of details,
A
Correspondence to: Edward Abraham, MD, FCCP, Pulmonary Science, Critical Care, Univ Colorado Health Science Center, 4200 E Ninth Ave, Denver, CO 80262
including hotels and catering, required for the success of the meeting. We would like to thank Marvin Schwarz, MD, FCCP, for his continuing devotion to the Aspen conference series. Mike Baird and Wayne Silvers again provided essential background help. As always, the conference would not have been possible without the continued support of the Francis Families Foundation and the many representatives of the pharmaceutical industry. Edward Abraham, MD, FCCP, Chair Lance Terada, MD, Co-Chair University of Colorado Health Science Center Denver, CO
41st Aspen Lung Conference: Overview* Thomas L. Petty, MD, Master FCCP
(CHEST 1999; 116:1S–2S) variety of catastrophic events have been known to lead to acute lung injury since World War I. Early terms for acute lung injury were “shock lung,” “postperfusion lung,” “traumatic wet lung,” and “congestive atelectasis.” These massive lung injury states were described only following autopsies. In the mid 1960s, the Denver group recognized a common denominator in patients who had suffered shock, trauma, overwhelming infections, and miscellaneous other conditions that resulted in the dramatic onset of acute respiratory distress, refractory hypoxemia, bilateral symmetric pulmonary infiltrates, and reduced lung compliance. Five of 12 patients survived with the application of mechanical ventilation and the use of positive end-expiratory pressure. This clinical state was first described as “acute respiratory distress in adults” and later as ARDS.1,2 The “adult designation,” however, was inappropriate, since the youngest patient in our original series was 11 years old, and the next oldest was 15 years old. The mean age was 29.4 years. In our original description of ARDS, we recognized surfactant defects in the two autopsy specimens studied
A
*From Presbyterian/St. Luke’s Hospital, Denver, CO. Correspondence to: Thomas L. Petty, MD, Master FCCP, University of Colorado Health Science Center, 1850 High St, Denver, CO 80218 CHEST / 116 / 1 / JULY, 1999 SUPPLEMENT
1S
and the presence of destructive proteolytic enzymes. In observing ARDS for . 30 years, a huge amount of basic science has identified a myriad of cellular and humoral mediators in acute lung injury, with a panoply of inflammatory cytokines and chemokines, while enhancing and inhibiting mediators of inflammation. Supportive care of patients during the past third of a century has improved to the point that . 50% can survive.3 Thus far, clinical trials investigating the efficacy and safety of new pharmaceuticals aimed at blocking the inflammatory mediators of disease have not proved successful.4 The development of an ARDS clinical trials consortium offers the machinery to test additional new therapeutic agents.5 Although it is doubtful that a single “silver bullet” will stop the cascade of events resulting in ARDS, it is possible that the replacement of surfactant in early stages or a combination of mediator blockers might alter the outcome of the basic biological processes resulting in ARDS. The first Aspen Lung Conference on ARDS was the 16th, in 1973.6,7 The second was in 1993.8 Now, 25 years later, the 41st Aspen Lung Conference has enlightened us further about the basic nature of ARDS. Future progress depends on the clinical application of new therapeutic agents aimed at the basic biological processes associated with ARDS. An imaginative approach to therapy is needed in the future.
References 1 Ashbaugh DG, Bigelow DB, Petty TL, et al. Acute respiratory distress in adults. Lancet 1967; 2:319 –323 2 Petty TL, Ashbaugh DG. The adult respiratory distress syndrome: clinical features, factors influencing prognosis and principles of management. Chest 1971; 60:233–239 3 Milberg JA, Davis DR, Steinberg KP, et al. Improved survival of patients with acute respiratory distress syndrome (ARDS): 1983–1993. JAMA 1995; 273:306 –309 4 Levy PC, Utell MJ, Sickel JZ, et al. The acute respiratory distress syndrome: current trends in pathogenesis and management. Compr Ther 1995; 21:438 – 444 5 Bernard GR, Artigas A, Brigham KL, et al. The AmericanEuropean Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 1994; 149:818 – 824 6 Petty TL, Hudson LD, Ashbaugh DG. The 16th Aspen Lung Conference. Chest 1974; 65(Suppl;part 1):1S– 67S 7 Petty TL, Hudson LD, Ashbaugh DG. The 16th Aspen Lung Conference. Chest 1974; 65(Suppl;part 2):1S– 46S 8 Petty TL. The acute respiratory distress syndrome: historical perspective. Chest 1994; 105(Suppl):44S– 47S
Lung Cytokines and ARDS* Roger S. Mitchell Lecture Thomas R. Martin, MD, FCCP
(CHEST 1999; 116:2S– 8S) 2S
cellular and molecular basis for ARDS remains T heuncertain . 30 years after the original description of the syndrome. With the explosion of information about the involvement of cells and cytokines in inflammation, there has been intense interest in understanding the involvement of cytokines in the pathogenesis of ARDS. Cytokines are low-molecular-weight soluble proteins (generally , 30 kda) that transmit signals between cells. It is now clear that cytokine production is not limited to lymphoid and myeloid cells, and that cytokines produced by epithelial and mesenchymal cells amplify inflammatory responses in the lungs and other organs. Cytokines are produced in “cascades” in which the initial cytokine signals are amplified many-fold by target cells, such as epithelial cells, fibroblasts, and endothelial cells. Cytokines function in “networks” in which feedback occurs at many points to coordinate and regulate cytokine and cellular responses. There are three major reasons to study the involvement of cytokines in patients with ARDS: first, to understand the pathogenesis of the disease; second, to identify markers that might be used to determine which patients are at highest risk for developing ARDS; and third, to identify markers that can predict outcome, including survival and/or long-term disability.1 Studies of single cytokines have shown that no single cytokine consistently predicts either the onset or the outcome of ARDS, despite promising early results. Instead, it is now recognized that a balance of proinflammatory and anti-inflammatory factors influences the net inflammatory response in the lungs.2 Current efforts are directed at defining the cytokine balance that exists in the lungs at the onset of ARDS, and how this balance changes over time.
Sampling and Measurement Considerations The study of cytokine balance in the lungs is difficult because of sampling and measurement issues. Experimental studies suggest that cytokine responses normally are compartmentalized in the lungs, and that the study of blood specimens provides an incomplete reflection of inflammatory events in the lungs.3 However, compartmentalization is lost to some extent during severe inflammatory responses.4 Thus, measurements of cytokines in the lungs are likely to be more valuable than measurements in plasma or serum. Sampling cytokines in the lungs is difficult, because cytokines function not only in the alveolar compartment, where they may exist as soluble constituents of alveolar fluids, but also in the tissue compartment, where they bind to components of the extracellular matrix. Thus, sampling alveolar fluids by direct aspiration of the distal airways or by BAL may provide incomplete information about the concentration and function of spe*From the Medical Research Service, Seattle VA Medical Center, and the Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington School of Medicine, Seattle, WA. Supported in part by grants HL30542, A129103, and GM37696 from the National Institutes of Health, and the Medical Research Service of the Department of Veterans Affairs. Correspondence to: Thomas R. Martin, MD, FCCP, Pulmonary Research Labs, 151L, Seattle VA Medical Center, 1660 S Columbian Way, Seattle, WA 98108; e-mail: [email protected] Thomas L. Petty 41st Annual Aspen Lung Conference: Acute Lung Injury