Lung transplantation is an option for appropriately selected patients with end-stage emphysema caused by alpha 1-antitrypsin deficiency. The functional results have been excellent after single or bilateral lung transplantation, and the medium-term survival results have been good. However, the role of alpha 1-antitrypsin replacement therapy after lung transplantation remains uncertain, and further investigation is needed.

alpha 1-Proteinase inhibitor (alpha 1-PI) augmentation therapy has been licensed for treatment of alpha 1-PI-deficient individuals with pulmonary emphysema. The currently available product is purified from pooled human plasma. To obtain larger amounts of protein free from possible unknown plasma contaminants, human alpha 1-PI has been produced by recombinant DNA. Since wild-type alpha 1-PI is susceptible to oxidative impairment, several alpha 1-PI variants in which the active site oxidation-sensitive residue is replaced by inert residues have been constructed. This article is aimed at reviewing the history, biological efficacy, advantages, disadvantages, and concerns linked to alpha 1-PI recombinant DNA and site-specific mutagenesis technology.

As in hereditary alpha 1-antitrypsin deficiency, protease-antiprotease and oxidant-antioxidant balances play a significant role in the pathogenesis of ARDS. However, the disease processes and possibilities for therapeutic intervention differ markedly.

In inflammatory lung disorders, oxidants and proteases complement each other in their potential to destroy lung parenchyma. It is therefore rational to combine therapeutic strategies aimed at augmenting the antiproteolytic defenses of the lung in diseases such as emphysema with antioxidant strategies. In the healthy lung, the oxidant burden is balanced by the local antioxidant defenses. However, both an increased oxidant burden and/or decreased antioxidant defenses may reverse the physiologic oxidant-antioxidant balance in favor of oxidants, leading to lung injury. This concept points to an obvious therapeutic strategy: augmentation of the antioxidant screen of the lung to prevent oxidant-mediated tissue damage. Studies using reduced glutathione (GSH), the major pulmonary antioxidant, as a model therapeutic agent demonstrated that GSH can be administered directly to the respiratory epithelial surface by aerosol and is fully functional as an antioxidant both in vitro and in vivo. In pulmonary diseases such as idiopathic pulmonary fibrosis or following HIV infection, GSH aerosol therapy not only normalized deficient pretherapy GSH levels in the lung, but was capable of favorably influencing cellular events such as oxidant release by pulmonary inflammatory cells. The same was true for oral antioxidant therapy with N-acetylcysteine, a glutathione precursor. These results suggest that it is possible to use antioxidants to reverse the imbalance between oxidants and antioxidants at the site of oxidant injury to prevent the progressive tissue damage in lung disorders characterized by high oxidant states. Antioxidants, alone and in combination with antiproteases, merit further long-term studies for clinical therapy.

Physiologically, secretory leukoprotease inhibitor (SLPI) is the major antiprotease of the epithelium of the upper respiratory tract providing protection against neutrophil elastase (NE). The recombinant form of SLPI (rSLPI) has several advantages compared with alpha 1-antitrypsin that make it interesting as potential therapy. In vitro, rSLPI proves to be an excellent inhibitor of NE. When administered as an aerosol in vitro and in vivo, the structure and function of rSLPI remain intact. Using the aerosol route, the half-life of rSLPI in respiratory epithelial lining fluid is 12 h; thus, giving it twice daily should guarantee satisfactory levels in the lung. Following inhalation, rSLPI moves from the epithelium in an intact form into the interstitium of the lung. Following on from these in vitro and in vivo experiments, a short-term study in patients with cystic fibrosis was performed with aerosolized rSLPI. Promising results relative to NE level reduction and the consequences for the inflammatory process in the bronchi were achieved. rSLPI not only induced an increase of the anti-NE protective screen, but also improved the antioxidant protection by raising glutathione levels in the lung in sheep. rSLPI may therefore provide a unique opportunity for protecting the lung from the damage caused by inflammatory processes by giving a single drug.

Cystic fibrosis (CF), the most common lethal genetic disease affecting the white population, owes its morbidity and mortality primarily to the devastating effects of chronic inflammation and infection within the pulmonary airways. It has become increasingly recognized that the host's response to Pseudomonas species and Staphylococcus aureus infection plays a paramount role in CF lung destruction and eventual development of respiratory insufficiency. A massive pulmonary influx of neutrophils, and accompanying excessive levels of neutrophil elastase (NE), can be detected in the bronchoalveolar fluid of even very young children with CF. The excess of NE adversely affects the CF airways by enhancing mucus secretion, directly injuring airway tissues, exacerbating the inflammatory process by attracting more neutrophils, and derailing opsonization and elimination of bacterial pathogens, particularly Pseudomonas aeruginosa. Neutralization of excess NE by delivering supplemental alpha 1-antitrypsin to the airways via aerosolization represents an exciting new potential therapy for CF lung disease.

alpha 1-Antitrypsin (alpha 1-AT) accumulates in the rough endoplasmic reticulum through a mechanism of polymerization. Polymerization is favored by the incorrect tertiary structure of the alpha 1-AT caused by a point mutation at position 342 of the protein. Accumulation of alpha 1-AT in the liver cells (and in hepatocytes and colangiocytes) is not sufficient per se to explain the liver disease that is manifested in a minority of PiZ subjects and thus, a trigger factor must be hypothesized. A virus (hepatitis C virus or some other kind of virus not identified as yet) is among the most probable trigger factors. In Z subjects (among the general population), relevant liver disease is probably a more rare event than thought in the past and most of these subjects escape major liver disease. Usually, liver disease is not a significant problem in patients with COPD.

The serpin family of protease inhibitors, to which alpha 1-antitrypsin belongs, has the unique feature of a mobile reactive center. Mutations within the critical regions of the molecule that control this mobility can allow premature changes in conformation with consequent abnormalities in folding and accompanying polymer formation. These abnormalities explain the plasma deficiency and liver inclusions associated with the common Z variant, as well as other variants of alpha 1-antitrypsin. The understanding of the molecular mechanisms provides a satisfying explanation for the clinical findings associated with these deficiency variants.

The early history of alpha 1-antitrypsin deficiency, in the years between 1962 and 1965, and its impact on the understanding of emphysema abnormalities were reviewed by me in 1989. This report discusses the disease spectrum (including emphysema, liver, and vasculitic diseases) and focuses on the variable clinical expression of the deficiency state. Some new findings that may be relevant to the function of alpha 1-antitrypsin are also considered.

Three asthmatic patients with dyspnea and episodes of apparent bronchospasm unresponsive to conventional therapy are described. During these episodes variable extrathoracic upper airway obstruction and airflow limitation typical of bronchial asthma were demonstrated by spirometry test results. In one patient, paradoxical vocal cord motion was identified by fiberoptic laryngoscopy. We believe these patients represent an unusual subgroup of asthmatic subjects who manifest laryngeal dysfunction. Recognition of this upper airway component to airflow limitation in some asthmatic patients may help physicians avoid potentially unnecessary therapy with systemic steroids and endotracheal intubation.

Pulmonary vascular inflammatory disorders may involve all components of the pulmonary vasculature, including capillaries. The principal histopathologic features of pulmonary capillaritis include capillary wall necrosis with infiltration by neutrophils, interstitial erythrocytes, and/or hemosiderin, and interalveolar septal capillary occlusion by fibrin thrombi. Immune complex deposition is variably present. Patients often present clinically with diffuse alveolar hemorrhage, which is characterized by dyspnea and hemoptysis; diffuse, bilateral, alveolar infiltrates on chest radiograph; and anemia. Pulmonary capillaritis has been reported with variable frequency and severity as a manifestation of Wegener's granulomatosis, microscopic polyarteritis, systemic lupus erythematosus, Goodpasture's syndrome, idiopathic pulmonary renal syndrome, Behçet's syndrome, Henoch-Schönlein purpura, IgA nephropathy, antiphospholipid syndrome, progressive systemic sclerosis, and diphenylhydantoin use. In addition to history, physical examination, and routine laboratory studies, certain ancillary laboratory tests, such as antineutrophil cytoplasmic antibodies, antinuclear antibodies, and antiglomerular basement membrane antibodies, may help diagnose an underlying disease. Diagnosis of pulmonary capillaritis can be made by fiberoptic bronchoscopy with transbronchial biopsy, but thoracoscopic biopsy is often employed. Since many disorders can result in pulmonary capillaritis with diffuse alveolar hemorrhage, it is crucial for clinicians and pathologists to work together when attempting to identify an underlying disease. Therapy depends on the disorder that gave rise to the pulmonary capillaritis and usually includes corticosteroids and cyclophosphamide or azathioprine. Since most diseases that result in pulmonary capillaritis are treated with immunosuppression, infection must be excluded aggressively.

Aortic dissection most often is an acute event dominated by excruciating pain and other symptoms which suggest the diagnosis. Our report and a review of the medical literature demonstrate that chronic aortic dissection may, rarely, present as a prolonged febrile illness, with night sweats, weight loss, pleural effusion, and little or no pain. These symptoms may be associated with a markedly elevated erythrocyte sedimentation rate (ESR), anemia of chronic disease, and hyperglobulinemia. Awareness of this unusual presentation, a high index of suspicion, and confirmation by an appropriate imagine technique (CT or MRI of the chest or transesophageal echocardiography have a very high sensitivity) will result in earlier diagnosis and better patient outcome.