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-2- INTEODUCTION The occurrence of emphysema of the lung has been associated with cigarette smoking (I, 2), although there is evidence that the susceptibility to emphysema is inherited (1). During about: the last twelve years stronE evidence has accumulated that a deficiency in the blood serum level of the enzyme al-antltrypsin (el-AT) pre-disposes people to emphysema, and thac it is this deficiency which can be inherited. Consequently, for individuals wiuh such a pre-d£sposition, smoking could be hazardous (2). It is obviously, in the interests of the tobacco industry to • ppreclate the large vol~me of research that is belnE carried out on of-AT, on the consequences of its deficiency, and on the genetics of its transm/ssion. In the lest two years, for example, at least 59 papers have been published on =I-AT. The present report reviews the available llt•rature on =l-AT. 1. Types of Emph_ysema Zn emphysema the lungs have lost much of chelr recoil capacity, and the force available to expel air ouc of the lungs is reduced (3). In addition, the airways inside the lung, having lost the support of the lung tissue, are narrower than normal at any given lung volume and offer a greater resistance to air flow. The volume of the lungs is often greatly increased, and a greater volume of air remains ~ them which cannot be exhaled. Emphysema is caused by desuructlon of alveolar tissue, which leads to emphysematous lungs having much enlarged air cavities, fewer alveolar walls than normal, within which the network • of capillary blood vessels in which the exchange of respiratory gases occurs is reduced. Emphysama can affect both Lungs, or part of • lung, BAT Co LTD - MINNESOTA TOBACCO LITIGATION r",o

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-3- or some regions of both lungs. The affected lungs of can do not collapse, as fs usuaL, when the thorax is opened during autopsy, 7et the lunS itself is not stiff but soft. The air does not come ouC of the lungs for reasons which are not fully understood. There are two main types of emphysema: centrilobular (or cencrlaclnar) emphysema, involving the central portion of the secondary lobule of the lung*, and panlobular (or panacinar) emphysema, involving all lobules of the lung. However, medical opinion is divided as to whether these two types are distinct diseases which affect different parts of individual lung lobules, or whether the only difference is the lobule affected, with no differences in onset, nature and duration of symptoms etc. (A). Alternative classifications of emphysema on the basis of the distribution and form of the enlargements ~rLChin the lung have also been proposed (5). External factors such as exposure Co coal and other dusts, and other pollutants, including those present in ciKareCte smoke, are considered by ~hacchinson (2), for example, co be important factors in the development of both types of emphysema. There ia also an apparently distinct clinical Kroup o£ people with emphysema who have a deficiency of el-AT in their blood serum, their el-AT levels being 10-20Z of that of the majority of the population (2). Furthermore, in these patients there is a strong tendency for the disease to have occurred in other members of the family, and for the lower zones of the lungs co be the most severely affected, and the main lesions generally have the features of panlobular emphysema. In emphysematous subjects wlCh normal el-AT levels, the lesions are found in the upper zones of the lunK in over half the cases. Wlth el-AT *The riKht funk consists of three lobes, and the left lung consists of two. BAT Co LTD - MINNESOTA TOBACCO LITIGATION "-.a

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-4- deficient patients, the onset of emphysema is usually between aaes 30 and 40 years) compared to beL~een 60 and 70 years for patients ~h normal el-AT levels (6). The course of deterioration of the lung function is usually more rapid than in patients with normal el-AT levels. Apart from these d~fferences) the broad similarities between the two groups of panlents sugaest that the biochemical and patholoSlcal processes which are responsible for emphysema have muuh in common, whether =l-AT is presenu in normal quantities or non. There is also a predominance of males who develop e.~physela) both with deficient and normal uI-AT levels. 2. a 1-anti~r~sin Proteases (i.e. protein-degrading enzymes) play an important part in various biochemical processes. Cernain proteins can inhibit pronease activity by combinin~ with the enzyme and inactivating it. The capacity of human blood serum to inhibit the enzymatic activiey of sc~e proteases has been known for almost eighty years (6). About 9Or of the serum's antlprotease activity derives from a &lycoprotein which forms most of the blood's =I sl°bulin" This substance is called a1-antitrypsin because its activity is usually quantified by measurement of its capacity to inhibit trypsin. Much of the remainder of the serum's inhibitory activity is due to a2-macroalobulin. Both this and at-AT ere active aaainst a number of proteases, includin8 trypsin) chymotrypsin) and elas~ase (2, 7). The reactions with trypsin and =hymotryps£n are apparently stoichic~etric (7). =I-&T is produced by the liver (8) and found in blood, semen, cervical mucus and other body fluids (9). It is a Elycoprorein with a carbohydrate portion of about 12~ containing galactoae, mannose, aceeyl BAT Co LTD - MINNESOTA TOBACCO LITIGATION rka -,,,,,/

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-5- hexosau~ne, sialic acid and fructose (6). The amino acid composition shows • high content of •8p•rtic acid (9.75X), glutamic acid (12.9Z) and leuclne (9.9Z). Cysteine is noc found, suggesting that at-AT does not contain disulphide bridges. Values for th• molecular v•LKht of =l-AT of between A5,000 and 54,000 have been quoted (7, 10-13). Xt has b••n isolated in pure form from human serum (13), and its physical properties suggest chat iC has a sinai• polypeptide chain. The amino acid sequence for the N-termL~al eight residues is: Glutamic acid ! "Aspartic acid I Pro i ine I Glutamine l Glycine l Asparagine + Aspartic acid [ Alanine I Al•r~ne =l-AT readily forms polymers and higher 8g@regates when exposed to denatur~K •gents. Its half-llfe in both normal and QI-AT deficient subjects has been estimated to b• approximately four to six days (1A, 15). A con~an£ent and widely used method for the determinatlon of the concentration of =I-AT in serum in the pr•senc• of other £nhibitors is radial /~n~nod~fusion (16). In this mJehod, • specific antistrum is incorporated /nto an as•rose Kel, samples axe appl£ed in wells, and the area of the circular inmunoprecipi~aut is proportional to the concentration of antisen present. With this method the concentration of •l-AT in BAT Co LTD - MINNESOTA TOBACCO LITIGATION

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~6m _I normal serum lies between 2.0 and 2.5 g £ (6, 15, 17) and tbls range satisfactorily accounts for the observed tTypsin £nhib£tion acCiv£L'y of serum if the reaction between trypsin and el-AT is stolchlometric (18). About 85-95X of people have this level of =l-AT, the exact proportion depending on the racial origin of the population (I9). The remainder of the population have various lower levels of =I-AT. The =l-AT concentration in blood can also be elevated by up to 5OZ under some condi=ions, e.g. during pregnancy and £n women .king oral contraceptives (6). 3. Genetic Transmission of el-AT Deficiency 3.1 Early Studies Tt was first reported in 1963 that some individuals have very low levels of =l-AT in their serum, approximately 10-20Z of normal (20). Subsequent studies suggested that the deficiency is inherited (21-24). All the available studies showed that when one parent has a low level and the other a normal level of =I-AT, all nhelr children have intermed£ate concentrations. Lf one parent has an intermediate and the other a normal concentration, approximately half ~he children have a normal concentration, and the other half have an intermediate concentration. This r.annot be explained by Mendelian genetics with one recessive and one dominant gate, since only normal individuals (containing either t~o dominant genes, or one dominant and one recessive gate) and deficient individuals (containin8 two recessive Series) would be observed. It was postulated that there were t~o codominant Kenes, with each sane resulting in =l-AT appearing in serum independently of the other. One sane contrlbutee about 50Z of the total normal el-AT concentration, and the mmmm~ BAT Co LTD - MINNESOTA TOBACCO LITIGATION

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