The origins of a concept: the protease-antiprotease imbalance hypothesis.

O ne of the more intense areas of research in lung disease in the past 40 years has been the investigation of mechanisms of lung parenchymal destruction by in vivo enzymatic proteolytic enzymes causing pulmonary emphysema and COPD. How this direction of research evolved is worth recounting because it illustrates how quite different experimental approaches done in different parts of the world at approximately the same time can give rise to new conceptual insights that point the way for what were then wholly new directions of research. The time is May 1958 at a meeting of the Association of American Physicians at the Haddenhall Hotel in Atlantic City. These meetings were annual pilgrimages by young and old alike who belonged to the “young young Turks” (the American Federation for Clinical Research), the “young Turks” (the American Society for Clinical Investigation), and the “old Turks” (the Association of American Physicians). The meeting was not the plenary session of the Association of American Physicians, but was the second day of meetings, where papers were presented to smaller groups in the solarium of the Haddenhall Hotel. On this day, a paper was presented from Lewis Thomas’s Department of Pathology at New York University by Robert McCluskey.1,2 The point of the paper was to demonstrate the ability of a crude protease, in this case papain, to degrade cartilage with great rapidity when injected intravenously. A dramatic example of this effect was shown at the meeting on slides showing that the ears of live rabbits could be made to collapse in a matter of hours postinjection through the degradation of cartilage and excretion of chondroitin sulphate in urine (Fig 1). It was also shown that the cartilaginous softening that resulted in ear collapse was reversible in 3 to 4 days, and that the rabbits ears were once again erect after that time, as a result of replenishment of ear cartilage with chondroitin sulphate. Here then was a demonstration of a rather specific effect of an enzyme on cartilage that could be applied to dissect the role of various connective tissue elements to the mechanical behavior of airways in the lung. While papain could be used to degrade cartilage of the mammalian trachea and bronchi, there were available other enzymes that were reasonably specific to degrade other connective tissue components, such as elastases from porcine or bovine pancreas and collagenase from clostridial organisms. Use of these enzymes in animal lungs demonstrated the rapid potency they possessed to degrade elastin and collagen, as well as cartilage, and the consequences of this degradation in terms of mechanical characteristics of distensibility and rigidity related to the changes in airway morphology.3–5 In 1963, Laurell and Ericksson6 published their classic article on the observation that members of families that have low concentrations of serum 1antitrypsin have a high prevalence of pulmonary emphysema in both male and female family members, and at ages much younger than the usual smoking population that acquired emphysema. Exactly how the inherited deficiency of this serum protein might be related to lung parenchymal destruction was evolving from laboratories in America. In 1965, Gross et al,7 from the University of Pittsburgh, demonstrated that papain and quartz dust degrade lung tissue of rats to produce parenchymal destruction resembling centrilobular and panacinar emphysema. Other enzymes such as -chymotrypsin with quartz dust did not produce emphysematous destruction. Why papain was selected for these studies is not stated, but papain is recognized to have potent elastolytic properties in tissue.8 *From the Department of Medicine, Columbia University College of Physicians and Surgeons, and James P. Mara Center for Lung Disease, St. Luke’s-Roosevelt Hospital, New York, NY. Manuscript received March 21, 2002; revision accepted April 23, 2002. Correspondence to: Gerard M. Turino, MD, Department of Medicine, Columbia University College of Physicians and Surgeons, St. Luke’s-Roosevelt Hospital, New York, NY 10019; e-mail: [email protected] special report