undivided 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 way of in vivo enzymatic proteolytic enzyme causing pulmonary emphysema and COPD for what reason this direction of research evolv is worth recounting because it illustrates for what reason quite different experimental approaches done in different parts of the world at approximately the same time can give rise to fresh conceptual insights that point the way for what were then wholly just discovered directions of research.

The time is May 1958 at a meeting of the Association of American Physicians at the Haddenhall public-house in Atlantic City. These meetings were annual pilgrimages by the agency of 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, yet was the second day of meetings, where papers were at handed to smaller groups in the solarium of the Haddenhall public-house On this day, a paper was at handed from Lewis Thomas's Department of Pathology at strange York University by Robert McCluskey. (12) The point of the paper was to demonstrate the ability of a harsh protease, in this case papain, to degrade cartilage with great rapidity when injected intravenously. A dramatic example of this purport was shown at the meeting upon slides showing that the ears of live rabbits could be made to collapse in a matter of hours postinjection by the and of the degradation of cartilage and excretion of chondroitin sulphate in urine (Fig 1) It was also shown that the cartilaginous softening that outcomeed in ear collapse was reversible in 3 to 4 days, and that the rabbits ears were one time again erect after that time, as a spring of replenishment of ear cartilage with chondroitin sulphate. Here then was a demonstration of a rather specific power of an enzyme on cartilage that could be applied to dissect the part of various connective tissue proper states to the mechanical behavior of airways in the lung

[FIGURE 1 OMITTED]

While papain could be used to degrade cartilage of the mammalian trachea and bronchi, there were available other enzyme that were reasonably specific to degrade other connective tissue ingredients such as elastases from porcine or bovine pancreas and collagenase from clostridial organisms. Use of these enzyme in animal lung demonstrated the rapid strength they possessed to degrade elastin and collagen, as well as cartilage, and the connections of this degradation in limits of mechanical characteristics of distensibility and rigidity related to the changes in airway morphology. (3-5)

In 1963 Laurell and Ericksson (6) published their classic article in succession the observation that members of families that have soft concentrations of serum [[alpha].sub.1]-antitrypsin have a high prevalence of pulmonary emphysema in the two male and female family members, and at ages plenteous younger than the usual smoking population that acquired emphysema. Exactly to what extent the inherited deficiency of this serum protein might be related to lung parenchymal destruction was evolving from laboratories in America.

In 1965 Gros et al, (7) from the University of Pittsburgh, demonstrated that papain and quartz dust degrade lung tissue of rats to originate parenchymal destruction resembling centrilobular and panacinar emphysema. Other enzyme similar as [alpha]-chymotrypsin with quartz dust did not breed emphysematous destruction. Why papain was excellented for these studies is not stated, if it were not that papain is recognized to have cogent elastolytic properties in tissue. (8)

according to the mid-1960s, Drs. Janoff and Scherer, (9) working at novel York University, demonstrated that the normal human neutrophil contained a powerful serine elastase. This elastase could therefore act forward lung tissue under normal circumstances, through access through the pulmonary vasculature and the normal circulatory cellular constituents traversing the lung Later studies were to point out that serum from patients with [[alpha].sub.1]-antitrypsin deficiency lacks inhibitory capacity specifically for elastase. (10) Later studies also elegantly demonstrated the morphologic and mechanical general intents of elastases in animal lung to originate a useful model of pulmonary emphysema using papain (11) and neutrophil elastase. (12) Thus, four places of observations all led to the protease/antiprotease imbalance hypothesis for the progression in a continuously ascending gradation of lung destruction in pulmonary emphysema: (1) a realization of the biological authority of elastases and other elastolytic enzyme for elastin degradation, (2) the identification of a protease that have a title toed elastolytic properties that could bring into view an animal model which approximated human emphysema, (3) the recognition that [[alpha].sub.1] antitrypsin was a major specific inhibitor for neutrophil elastase, and (4) the demonstration that a genetically determined deficiency of serum [[alpha].sub.1]-antitrypsin was associated with the disclosure of pulmonary emphysema at a young age in nonsmokers and smokers

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