The Dichotomy Between Understanding and Treating Emphysema

The long history of investigations into the causes and potential treatments of emphysema encompasses a vast array of chemical and biological research disciplines. A key finding that played a major role in initiating these inquiries occurred in 1963 when Laurell and Eriksson[1] found that individuals with a genetic deficiency in serum alpha-1-antitrypsin (AAT) were prone to develop pulmonary emphysema[2]. This genetic linkage was given a mechanistic basis when Turino and colleagues in 1969 discovered that patients with reduced inhibition of pancreatic elastase also lacked serum AAT and were prone to develop severe pulmonary emphysema[3]. Subsequent studies in the early 1970s confirmed that excessive elastase activity due to lack of AAT was in fact the genetic mechanism responsible for the onset of emphysema [4-7]. A key environmental connection was made with the discovery that cigarette smoke increased macrophage secretion of elastase[8] in the lungs, oxidized AAT[9], and that the chemical irritants in smoke recruited neutrophils to the lungs via chemotaxis[10-12]. This integrated genetic-environmental understanding firmly established elastase inhibition as a mechanistic target for preventing the alveolar destruction characteristic of emphysema.