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Neutrophil elastase (NE) is the most important protease of the human lung; if not inhibited NE is able to attack nearly all structural proteins and components of the immune system of the lung. In the normal human lung this is prevented by an excess of protease inhibitors. Based on quantitative and kinetic analyses alpha 1-antitrypsin (AAT) is the most important protease inhibitor of the human lung followed by the Secretory Leukoprotease Inhibitor (SLPI). As protease inhibitors may be inactivated by proteases and reactive oxygen metabolites released from polymorphonuclear cells, it is not surprising that some lung diseases--in particular lung emphysema caused by AAT deficiency, cystic fibrosis and ARDS--are characterized by an imbalance between proteases and protease inhibitors. Because uninhibited NE seems to play an important role in the pathogenesis of these diseases, it is obvious to use protease inhibitors as drugs. Up to now in most studies in men AAT purified from human plasma has been used: worldwide a substantial number of patients with lung emphysema caused by AAT deficiency is treated continuously; in addition AAT was aerosolized to patients with cystic fibrosis in a short term study with results suggesting that this therapy is efficient at least on a biochemical basis. We performed in vitro and in vivo animal studies with the recombinant form of SLPI (rSLPI). In these experiments we found that aerosolized rSLPI a) is not altered in its form or function in the first 13 h following aerosol; b) has a half-tie of 12 h in the lung; c) reaches the interstitium of the lung in intact form.(ABSTRACT TRUNCATED AT 250 WORDS)

In patients with severe alpha-1-protease inhibitor (alpha 1-Pi) deficiency forced expiratory volume in 1 s (FEV1) is an accepted parameter to monitor the progression of emphysema. In a patient with severe alpha 1-Pi deficiency (PiZZ) more than 1,000 FEV1 measurements were performed over a period of 12 years. FEV1 dramatically decreased initially (delta FEV1 > 500 ml/year), but stabilized after augmentation therapy was instituted. Three years later, the FEV1 decreased again abruptly; the deterioration was paralleled by an increasing number of severe bronchopulmonary infections. This nonlinear decline implies a positive influence of augmentation therapy and a deleterious effect of bronchopulmonary infections in the disease (p < 0.0005). Daily variation of FEV1 in infection-free intervals exceeded 30% and were thus higher than the mean decrease in FEV1 per year. In this instance, FEV1 measurements performed once or twice per year may reveal a deterioration, whereas the change of FEV1 is still within the range of spontaneous variation. More frequent measurements of FEV1 can be useful to minimize the influence of high intraindividual variation.

Alpha 1-proteinase inhibitor (alpha 1-PI) has been demonstrated to suppress mitogen-induced lymphocyte response in vitro. To evaluate the effect of intravenous application of human alpha 1-PI (Prolastin HS) on cellular immunity, we determined total lymphocyte count, lymphocyte subsets and lymphocyte response to concanavalin A, before and 24 h after infusion of 60 mg.kg-1 body weight alpha 1-PI in eight patients with homozygous alpha 1-PI deficiency (PiZ phenotype). The results were compared with two blood samples from seven healthy controls. After infusion, serum alpha 1-PI levels were increased from 0.98 +/- 0.24 to 2.68 +/- 0.51 g.l-1. No significant differences were found for total lymphocyte count, lymphocyte subsets and lymphocyte response between both groups in both samples. Maximum 3H-thymidine incorporation before and after infusion showed no significant difference; the same was true for the two control samples. However, additional incubation in vitro with alpha 1-PI 5 g.l-1 led to a significant (p < 0.03) decrease of lymphocyte proliferation in samples after infusion. Our data indicate that alpha 1-PI substitution therapy does not lead to a major suppression of lymphocyte response to concanavalin A in PiZ individuals in vivo, although a suppressive effect was found after additional in vitro incubation with alpha 1-PI.

Emphysema is characterized by permanent enlargement of the respiratory air spaces distal to the terminal bronchioles accompanied by destruction of their walls and without obvious fibrosis. We present a review of this disease, discussing its classification, pathology, and therapy.

According to clinical characteristics and serum levels of alpha 1-proteinase inhibitor in the acute period (1-3 days), four groups of patients with myocardial infarction were identified. The most severe myocardial infarction was observed in patients from Groups 1 and 4. It was found that the serum alpha 1-proteinase inhibitor ratios in acute myocardial infarction were closely related to its clinical course. In the authors' opinion, determination of alpha 1-proteinase inhibitor titers by the rapid method will allow the goal-oriented therapeutical measures, including inhibitor therapy to be used.

Alpha 1-proteinase inhibitor (also known as alpha 1-antitrypsin) derived from pooled human serum (Prolastin, Miles Biologicals) has been available in the United States since 1988. Although no formal controlled prospective study has been performed to prove its efficacy, intravenous administration of Prolastin has been the accepted treatment for individuals with pulmonary emphysema due to alpha 1-antitrypsin deficiency. In addition, Prolastin has been used experimentally by inhalation for the treatment of cystic fibrosis. It has been administered with some success to treat the panniculitis associated with alpha 1-antitrypsin deficiency. As a greater number of severely impaired alpha 1-antitrypsin deficient patients receive lung transplantation, the role of Prolastin in the post-transplant therapy of these patients will need evaluation. Newer antiproteases may render Prolastin obsolete with respect to its route of administration and its pricing, however, the safety record of this drug has been impressive.

Alpha 1-proteinase inhibitor (alpha 1-PI), a serine protease inhibitor, was tested for its efficacy for the treatment of recalcitrant atopic dermatitis. Atopic dermatitis affects both children and adults and has no established etiology. We hypothesized that during inflammation there is an excess of serine proteases and a deficiency of their naturally occurring inhibitors at the local site of tissue injury, even though there is a normal serum level of serine protease inhibitors. This pilot study consisted of a nonblinded trial using alpha 1-PI at a concentration of 20 mg/mL in an aqueous solution in an alternate day schedule in conjunction with a 1% cream of alpha 1-PI (Stage I) and a 5% cream of alpha 1-PI for maintenance therapy (Stage II). Before enrollment in this trial all six patients failed to respond to high potency topical steroids. Safety was gauged by careful clinical monitoring of subjective complaints, objective findings of erythema, edema, and serial measurements of blood chemistries and complete blood counts. Wound healing was documented by serial photography. Written informed consent was obtained from each patient. All six patients showed significant clinical improvement within 6 to 21 days of initiation of alternate day therapy. Alpha 1-PI stopped pain, pruritus, and promoted tissue healing without scarring in all six patients. No adverse side effects of therapy were documented by clinical history, physical examination, or by blood studies after 120 days of therapy. Atopic dermatitis may be one example where inflammation is due to an imbalance of serine proteases and their naturally occurring inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)

Deficiency of alpha 1-protease inhibitor is a dominant autosomally inherited error of metabolism leading to destruction of alveolar septa by proteolytic enzymes mainly released by neutrophils often before the fifth decade. Diagnosis and determination of phenotype are achieved by serologic tests. Affected individuals have to be informed about the accelerated evolution of the lung disease by smoking and the possibility of therapy by substitution. The latter aims at maintenance of anti-proteolytic serum levels compatible with arrest of emphysema by weekly to monthly injections of human alpha 1-protease inhibitor as we illustrate with a case-report. In the future antiprotease produced by gene-technology, the application via aerosols or an infection of endothelial cells with viruses transferring genes for antiprotease may be possible.

The authors treated destructive forms of acute pancreatitis for the first time by means of specific plasma sorption of proteinases with the use of a proteinase plasma sorbent which is an acid-stable proteinase inhibitor immobilized on sepharose (ASI-Sepharose). Specific plasma sorption of proteinases on ASI-Sepharose was applied to the treatment of 29 patients with various forms of acute destructive pancreatitis. At the end of specific plasma sorption procedure the activity of blood plasma proteolytic enzymes in the patients reduced by 60-75%, which was attended by marked improvement of the condition in most cases; aggravation of the patients' condition was not encountered. The mortality in this group was 20.7% and was due to complications occurring during the development of the main disease. The mortality rate among patients treated by specific proteinase plasma sorption is much lower than that recorded in the USSR for destructive forms of acute pancreatitis which ranges from 30 to 75%.

Background: Alpha 1-antitrypsin (AAT) replacement therapy is an expensive intervention ($20,000-$30,000 per patient annually) which may slow or arrest the progression of chronic obstructive pulmonary disease (COPD) in AAT-deficient patients. While FDA-approved, therapy efficacy is unknown. The costs and benefits of AAT replacement therapy were evaluated for patients with congenital COPD., Methods: Epidemiological and disease cost data were taken from published sources. A discrete-time model of disease stage probability transition was developed to calculate the present-value expected cost of disease treatment, under a range of possible therapy efficacy and other parameter values., Results: At an efficacy of 70 percent, the cost per life year saved with AAT replacement therapy would be between $28,000 and $72,000 (1990 US dollars), depending on patient age, sex, and smoking status. At 30 percent efficacy, the cost per life year saved range would be between $50,000 and $128,000. A controlled efficacy study would cost $53 million or less, if the true efficacy were 50 percent or better., Conclusions: With efficacy of 30 percent or higher, therapy cost-effectiveness would be comparable to other widely used medical interventions. The economic assessment methodology was used to evaluate both the therapeutic innovation and the value of additional clinical research.

In cystic fibrosis neutrophil-dominated inflammation on the respiratory epithelial surface results in a chronic epithelial burden of the destructive enzyme, neutrophil elastase. alpha 1-antitrypsin (alpha 1AT), the main inhibitor of neutrophil elastase in lung, was given in aerosol form to 12 cystic fibrosis patients. It suppressed neutrophil elastase in the respiratory epithelial lining fluid (ELF) and restored the ELF anti-neutrophil elastase capacity when ELF alpha 1AT reached 8 mumol/l. This treatment also reversed the inhibitory effect of cystic fibrosis ELF on pseudomonas killing by neutrophils, which suggests that it may augment host defence in cystic fibrosis.

Inherited defects of the gene coding for a serum protein that protects alveolar walls from proteolysis constitute one cause of emphysema, with or without liver disease. The deficiency can be reversed with intravenous administration of the antiprotease, keeping serum levels above the minimum needed for lung protection.

In canine pancreatitis, irreversible hypotension and death follow saturation of the antiprotease molecules in peritoneal exudate by activated proteolytic enzymes which are released from the pancreas. This study has examined, in rats with taurocholate-induced pancreatitis, the efficacy of removal of the peritoneal exudate by aspiration and a single lavage, followed by instillation of an exogenous antiprotease solution. Instillation of human fresh frozen plasma, containing alpha 2-macroglobulin and alpha 1-antiprotease, was associated with the longest median survival. Aprotinin, although possessing a much greater trypsin inhibitory capacity, just failed to significantly improve the median survival time compared with the control group. Intraperitoneal antiprotease therapy is simple to perform, has a beneficial effect on survival time in this model and merits investigation in man.

Alpha 1-antitrypsin (alpha 1-AT) deficiency can cause a lung disease that, until a few years ago, has proved fatal to all patients diagnosed with this disease. This deficiency can now be treated with alpha 1-proteinase inhibitor, a protein derived from human plasma and delivered via intravenous infusion. Infusion therapy for alpha 1-AT deficiency can be delivered in the hospital or home environments. This article discusses the pathophysiology of alpha 1-AT deficiency and outlines nursing considerations for the intravenous clinician who is administering this therapy.

Plasma-derived alpha 1-proteinase inhibitor (alpha 1PlI) is used for replacement therapy in patients with emphysema who have a deficiency of the protein. Future therapy with alpha 1PI with reactive site mutants of this inhibitor will probably require the use of recombinant-derived alpha 1PI (r alpha 1PI). However, the pharmacologic efficacy of r alpha 1PI in humans has been hindered, since r alpha 1PI is rapidly cleared from the circulation of experimental animals. Our studies of the metabolism of r alpha 1PI in mice demonstrate that the rapid clearance of r alpha 1PI is due to renal filtration. However, after preventing renal filtration by ligation of the renal arteries, we find that r alpha 1PI is metabolized in a manner similar to alpha 1PI. Conjugation of r alpha 1PI to polyethylene glycol of Mr approximately 4000 (PEG-4) greatly slows the clearance of r alpha 1PI. The PEG-4 r alpha 1PI conjugate is metabolized in a manner similar to alpha 1PI and has similar kinetic properties before and after oxidation with N-chlorosuccinimide. Moreover, proteinase complexes of PEG-4-r alpha 1PI are catabolized by the same hepatocyte receptor that binds alpha 1PI-proteinase complexes. The results of these studies lay the groundwork for the synthesis of pharmacologically effective r alpha 1PI derivatives with acceptable plasma retention times.

A study was undertaken to determine whether emphysema and airway secretory cell metaplasia, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be moderated by pretreatment with human alpha 1-protease inhibitor (API). API (4.9 mg) was given intratracheally to hamsters 1 h before 0.3 mg HNE. Eight weeks later, lung volumes and pressure-volume relationships were measured in the anaesthetized animals. Mean linear intercepts and secretory cell indices were measured in lung sections. API given 1 h before HNE moderated the development of bronchial secretory cell metaplasia. The severity of emphysema was reduced by 75%. Clearance studies indicated that 80% of the functional activity of instilled API could be lavaged from the lungs after 1 h, indicating a 4 h half-life in the lavageable compartment of the lungs. We calculate that for 50% protection from emphysema the molar ratio of lavageable API to HNE at the time of HNE instillation was 4.8 as compared with 0.78 for 50% inhibition of elastolytic activity in vitro, indicating that API is only 16% as efficient in vivo as compared with its in vitro HNE inhibitory effectiveness. Nevertheless, we conclude that human API given intratracheally is efficacious against HNE-induced emphysema and secretory cell metaplasia.

Homozygous PiZZ individuals with a serum deficiency due to a defect in the secretion of the alpha 1-antitrypsin protein are at risk of developing severe panlobular emphysema. Tobacco smokers are particularly exposed to the disease which begins at an earlier age. Treatment by substitutive therapy with alpha 1-antitrypsin concentrates seems to be the only possibility. A two years' clinical trial was performed in 9 PiZZ patients, with more than 1,500 infusions being administered weekly. Serum AAT levels were used as guidelines to follow biochemical changes in the protease-antiprotease balance. From 0.16 g/l initially, the AAT level rose to 0.57 g/l after 7 months. No adverse reaction was observed during the trial; the concentrated protein was well accepted, ant the antielastase activity of the protein recovered after injection was equivalent to the activity injected. An attempt to administer the infusions monthly was stopped when we observed a dramatic decrease of the serum AAT level. Clinically, stabilization of the symptoms was noted. No degradation was observed in the patients who took part in the trial, even if no real improvement was detected.

Intravenous augmentation therapy with human plasma alpha 1AT represents the current "state of the art" form of therapy for alpha 1AT deficiency. Augmentation therapy is directed towards specific correction of the central abnormality of alpha 1AT deficiency i.e., to correct the insufficient anti-neutrophil elastase screen of the lung. By augmenting lung levels of functional alpha 1AT, the anti-neutrophil elastase protective screen of the lower respiratory tract is re-established, and the delicate alveolar structures are protected from elastolytic degradation. Weekly, monthly and plasma exchange-alpha 1AT infusion all share the same basic approach to augmenting lung anti-elastase defenses, and appear to be equally effective in re-establishing the anti-elastase screen of the lower respiratory tract. One important issue concerning augmentation therapy is the question of when to initiate therapy. Because the goal of augmentation therapy is to prevent lung destruction, it is rational to initiate therapy prior to the onset of significant lung destruction. Traditionally, pulmonary function testing and chest X-rays have been used to determine the degree of emphysema, but these methods are relatively insensitive when compared to newer evaluative methods, including computed tomography and ventilation-perfusion scanning. In view of the availability of these newer diagnostic modalities, and the desire to maximally preserve the lung through early initiation of augmentation therapy, the traditional concepts requiring the presence of lung function abnormalities as evidence of lung destruction may need to be re-evaluated for individuals with alpha 1AT deficiency. Aerosol augmentation therapy with human plasma alpha 1AT or with rAAT are attractive possible alternative approaches to increasing lung anti-neutrophil elastase defenses.(ABSTRACT TRUNCATED AT 250 WORDS)

Eight patients suffering from alpha 1-protease inhibitor (alpha 1-PI) deficiency (Pi ZZ phenotype) and chronic obstructive lung disease received substitution therapy (60 mg.kg-1 weekly) for a period of up to 30 months. Intrathoracic gas volume, airway resistance and arterial oxygen tension were followed once every three months. There was no trend for these indices to deteriorate or improve over the period of observation.

alpha 1-Antitrypsin (AAT) has been purified from human plasma supernatant A (equivalent to COHN fraction II + III) by a large-scale chromatographic procedure involving anion-exchange adsorption on DEAE Sepharose CL-6B fast flow and size-exclusion chromatography on Sephacryl S-200. Before freeze-drying, the liquid concentrate was heat-treated at 60 degrees C for 10 h to reduce the risk of transmission of blood-born viral diseases. Using this procedure, AAT is recovered with 80-90% purity in 65-75% yield from supernatant A. The heterogeneity of AAT is preserved across the purification steps. In addition, purified AAT exhibits inhibitory activities against trypsin and elastase equivalent to that of the serum protein. The mean association rate constant for elastase was found as high as 2.15 X 10(5) M-1 s-1. Thus, purifying active AAT from supernatant A contributes to improving the availability of this protein which may be potentially useful in the treatment of hereditary emphysema.

The null-null phenotype of alpha 1-antitrypsin (alpha 1AT), a phenotype characterized by no detectable alpha 1AT in serum, presents a rare opportunity to examine the contribution of alpha 1AT to the antineutrophil elastase protection of the lower respiratory tract. The subject, a 35-yr-old lifetime non-smoker with moderate emphysema, has been characterized as having alpha 1AT serum levels of zero resulting from the homozygous inheritance of alpha 1AT genes that do not express detectable alpha 1AT mRNA transcripts. Evaluation of the antineutrophil elastase capacity of the null-null serum showed it was less than 5% of normal, whereas that of the epithelial lining fluid (ELF) of the lower respiratory tract was 13% of normal. However, after 60 mg/kg of intravenously administered alpha 1AT augmentation therapy once weekly for 4 wk, the serum alpha 1AT levels peaked at greater than 300 mg/dl, trough levels just prior to the next infusion were 81 +/- 2 mg/dl, and the average serum level integrated for the month of infusions was 138 mg/dl. Consistent with this serum rise in alpha 1AT, the serum antineutrophil elastase capacity increased in parallel(r = 0.98). Importantly, evaluation of the ELF 2 and 6 days after infusion demonstrated increases of alpha 1AT levels (range, 1.4 to 2.1 microM) and antineutrophil elastase capacity (range, 1.6 to 2.5 microM), values within the lower range of normal. Furthermore, the lung ELF alpha 1AT levels rose in direct proportion to the serum alpha 1AT levels, and the ELF antineutrophil elastase capacity rose in direct proportion to the ELF alpha 1AT levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Human polymorphonuclear leukocyte elastase is the enzyme primarily responsible for the destruction of lung tissue observed in pulmonary emphysema. A number of potent reversible and irreversible inhibitors have been developed for human leukocyte elastase. Several of these inhibitors have been shown to be effective at preventing emphysema in animal models of the disease. There are excellent prospects for the development of a synthetic elastase inhibitor for use in treatment of human disease.

The current state of knowledge of contact coagulation pathways activated by exposure of blood to foreign surfaces such as occur with endothelial damage is reviewed. Changes in the contact proteins in normally occurring and experimentally induced infections in humans are summarized. The use of mutant alpha 1-antitrypsin to inhibit activation of this pathway in experimental porcine sepsis is also described. The principles developed may be applicable in studies of the pathogenesis and treatment of viral hemorrhagic fevers.

The in vitro properties of two peptide aldehydes are described which relate to their potential use as elastase inhibitors in the treatment of emphysema. When compared with alpha 1-antitrypsin they demonstrate potential advantages in terms of potency, specificity and stability to cigarette smoke.

We propose that alpha-1-protease inhibitor (alpha 1 PI) can assume a major and beneficial role in preventing emphysema in alpha 1 PI-deficient individuals, and may also prove of value in the treatment of adult respiratory distress syndrome (ARDS). alpha 1 PI has a single, unusual disulfide bond that consists of a cysteine residue in the peptide chain covalently bound to a free amino acid cysteine. The linkage can be broken by reductants without adversely affecting the stability or the inhibitory activities of the protein. As a result of this property, alpha 1 PI can be effectively separated in solution from many other plasma proteins by salting out the contaminants in the presence of strong reductants. We have applied the technique of reductive-salting out, coupled with more conventional DEAE-anion exchange chromatography to isolate alpha 1 PI from Cohn Fraction IV-1, a relatively unused side product in the worldwide production of albumin and immunoglobulins. Furthermore, we have demonstrated that the product can be effectively pasteurized in the presence of various stabilizing additives. The necessary ingredients now exist for extensive clinical studies in the years ahead.

The primary function of alpha 1-antitrypsin (alpha 1-AT), an antiprotease produced by the liver, is the inhibition of neutrophil elastase, a protease capable of hydrolysing most connective tissue components. The importance of alpha 1-AT is demonstrated by the high incidence of early-onset emphysema in individuals with hereditary alpha 1-AT deficiency (Type PiZZ), in whom serum levels of alpha 1-AT are 10-20% of normal. Oxidants in tobacco smoke can inactivate alpha 1-AT in vitro, and studies have shown that alpha 1-AT from the lungs of individuals who smoke cigarettes may also be partially inactivated, perhaps explaining the high incidence of emphysema associated with cigarette smoking. Oxidative inactivation is probably due to modification of the Met residue (Met358) at the P1 subsite position of the elastase binding site of the protein. To study the possibility of modulating the biological properties of alpha 1-AT, we have introduced selected sequence modifications at the reactive site by in vitro mutation of a cloned alpha 1-AT complementary DNA. We describe here the characterization of two alpha 1-AT analogues produced in Escherichia coli. The first, alpha 1-AT(Met385----Val), is not only fully active as an elastase inhibitor but is also resistant to oxidative inactivation. The other, alpha 1-AT(Met358----Arg), no longer inhibits elastase but is an efficient thrombin inhibitor. The active site of the latter is identical to that of the alpha 1-AT (Pittsburgh) variant, which was associated with a fatal bleeding disorder.

The emphysema associated with the inherited serum deficiency of alpha 1-antitrypsin appears to result from an imbalance between neutrophil elastase and its major inhibitor within the alveolar structures. In the present study we assessed the feasibility of reversing this biochemical defect within the lung via parenteral replacement therapy with an alpha 1-antitrypsin concentrate of normal plasma. A 20--40% polyethylene glycol precipitate of pooled human donor plasma was used to obtain an enriched alpha 1-antitrypsin concentrate devoid of hepatitis B antigen and immunoglobulins. Using this material, five individuals with severe serum alpha 1-antitrypsin deficiency (PiZ phenotype) and advanced emphysema received 4 g of alpha 1-antitrypsin intravenously at weekly intervals for four doses. During this period of weekly replacement therapy alpha 1-antitrypsin serum levels were maintained at greater than or equal to 70 mg/dl, the level likely required for effective antielastase protection of the lung. In addition, assessment of lower respiratory tract antielastase activity by bronchoalveolar lavage demonstrated that parenteral replacement of alpha 1-antitrypsin resulted in establishment of effective antielastase activity within the alveolar structures. There were no untoward side effects consequent to this approach to the replacement therapy of alpha 1-antitrypsin. These results demonstrate that the parenteral replacement of alpha 1-antitrypsin provides a means of obtaining elastase-antielastase balance within the lung of individuals with this serum protease inhibitor deficiency.

Alpha-1-antitrypsin (A1AT) deficiency is a genetic disorder characterized by low serum levels of A1AT and a high risk for the development of emphysema. A1AT is the principal inhibitor of neutrophil elastase, such that a deficiency of A1AT results in insufficient anti-elastase protection in the lower respiratory tract, thus allowing neutrophil elastase to destroy alveolar structures. The goal of A1AT augmentation therapy in A1AT deficiency is to raise lung A1AT levels and anti-neutrophil elastase capacity to levels that will provide adequate protection against neutrophil elastase, thereby preventing the lung from further elastase-mediated degradation. Studies with intravenous administration of human A1AT (60 mg/kg at weekly intervals) demonstrate that serum A1AT levels increased from an average 33 +/- 8 mg/dl pre-infusion to a steady-state trough level of 117 +/- 4 mg/dl, well above the projected threshold protective serum level of A1AT. The infused A1AT diffused into the lung and significantly augmented the epithelial lining fluid A1AT levels, rising from an average 0.44 +/- 0.16 microM (pre-infusion) to 2.62 +/- 1.29 microM at the nadir level just prior to the next infusion. Of critical importance is the fact that the A1AT that diffused into the lung was active as an inhibitor or neutrophil elastase, resulting in significant augmentation of epithelial lining fluid anti-neutrophil elastase capacity and normalization of the lung anti-elastase protection. In the over 800 weekly infusions administered, no significant adverse reactions have occurred. These findings demonstrate that long-term augmentation therapy with weekly infusions of A1AT is a rational, safe, and biochemically effective therapy for A1AT deficiency.

alpha 1-antitrypsin (alpha 1AT) deficiency is an inherited disorder almost always associated with the development of panacinar emphysema in the fourth to fifth decades. One source of alpha 1AT for chronic replacement therapy of such individuals is that produced by E.coli directed by a cDNA coding for the human alpha 1AT molecule. Using TG1(E.coli), an alpha 1AT molecule produced by E.coli transformed with the plasmid-expressing vector pTG922, the present study shows that recombinant DNA-directed E.coli-produced alpha 1AT is as an effective inhibitor of neutrophil elastase as alpha 1AT purified from plasma. Importantly, TG1(E.coli) inhibited human neutrophil elastase with an association rate constant of 1.3 +/- 0.4X10(7) M-1 sec-1, similar to that of normal plasma alpha 1AT (1.1 +/- 0.1, p greater than 0.2). Furthermore, when TG1(E.coli) was added to alpha 1AT-deficient plasma obtained from homozygous alpha 1AT type Z individuals, the TG1(E.coli) remained functional and augmented the anti-neutrophil elastase activity of the serum proportional to the amount of TG1(E.coli) added. These observations suggest that if sufficient amounts of recombinant DNA methodology-produced alpha 1AT molecules could be safely delivered to the alveolar structures of alpha 1AT-deficient individuals, they would function to protect the alveolar walls from elastolytic attack.