Marc M. Dunn

Pulmonary complications of amiodarone toxicity

A MIODARONE HYDROCHLORIDE, a benzofurone derivative, has been used since 1969 for the control of cardiac arrhythmias in the United States. It appears to be uniquely effective for some patients with refractory ventricular arrhythmias. Although serum levels in the range of 1.0 to 2.5 pg/mL have been considered therapeutic,’ amiodarone concentrations in tissues such as fat, skin, and lung may be many times greater. A variety of side effects have been noted following use of this drug, including corneal microdeposits, alteration of thyroid function, dermatitis, pseudocyanotic skin discoloration, hepatic dysfunction, proximal muscle weakness, and peripheral neuropathy. Pulmonary complications were not appreciated until 1980, when the first report of suspected pulmonary toxicity appeared.2 Since then there have been a number of articles describing pulmonary toxicity due to this agent in Europe and the United States. The magnitude of the problem of pulmonary toxicity is difficult to determine. The literature is primarily one of case reports and the criteria used to make the clinical diagnosis of amiodarone pulmonary toxicity are imprecise and inconstant. There is no hallmark of this complication short of pulmonary histology, and lung biopsy has not been performed routinely. Patients receiving amiodarone commonly have a history of clinical conditions, including congestive heart failure, which may be difficult to distinguish from amiodarone lung toxicity. Furthermore, alterations in pulmonary function may occur in some amiodarone treated patients without other clinical manifestations of pulmonary toxicity. All of these factors make it difficult to estimate the incidence of clinically significant amiodarone pulmonary toxicity. Key features that should be used in defining this entity in future studies include: (1) biopsy evidence of alveolitis, (2) diffuse pulmonary infiltrates or infiltrates involving the upper lung zones, (?) dyspnea and cough, (4) exclusion of other conditions likely to produce the clinical picture including congestive heart failure, infection, and collagen vascular disease, and (5) improvement after stopping or decreasing the dose of amiodarone. With these provisos in mind, the best estimate of the incidence of clinically significant amiodarone pulmonary toxicity in the United States is 5% to 15%.3-‘2 It should be noted, however, that autopsy studies suggest this condition may be underdiagnosed.

Asbestos-induced injury to cultured human pulmonary epithelial-like cells: role of neutrophil elastase

The mechanisms responsible for asbestos‐ induced pulmonary epithelial cell cytotoxicity, especially oxidant‐independent mechanisms, are not established. We determined whether human polymorphonuclear leukocyte (PMN) proteases contribute to asbestos‐induced damage to human pulmonary epithelial‐like cells (PECs) assessed using an in vitro chromium‐51 release assay. Serine antiproteases, phenylmethylsulfonyl fluoride and αι ‐antitrypsin, each ameliorated PEC injury induced by amosite asbestos and PMNs. A role for a specific proteinase, human neutrophil elastase (HNE), is supported by the facts that (1) asbestos increased HNE release assessed by an enzyme‐linked immunosorbent assay technique (1.7 ± 0.5 vs. 2.8 ± 0.5 μg/ml; P < .025), (2) purified HNE or porcine pancreatic elastase (PPE) each alone caused PEC detachment, (3) asbestos plus either HNE or PPE caused PEC lysis similar to that mediated by asbestos and PMNs, and (4) cationic agents released from PMNs were unlikely to be involved because polyanions did not ameliorate injury resulting from asbestos and PMNs. Compared to elastase, cathepsin G caused less PEC detachment and negligible augmentation in asbestos‐ induced PEC lysis. Asbestos increased the association of 125I‐labeled elastase with PECs nearly 50‐fold compared with PPE alone (14.4% vs. 0.3%, respectively; P < .01) and nearly 10‐fold compared with another particle, opsonized zymosan. We conclude that PMN‐derived proteases, especially elastase, may contribute to asbestos‐ induced lung damage by augmenting pulmonary epithelial cell injury.