Pulmonary emphysema, defined as airspace enlargement distal to terminal bronchioles, is a major component of chronic obstructive pulmonary disease (COPD). COPD is currently the fourth leading cause of death in the US, with a worldwide epidemic looming as an addicted humankind enthusiastically lights up its cigarettes. To make matters worse, short of lung transplantation and volume reduction surgery, we have little to offer these patients, other than oxygen, as they grasp for each breath. Improved understanding of the biological basis of this disease is required if we hope to intervene. Two observations made in the early 1960s, one clinical and one experimental, form the cornerstone of our current understanding of emphysema. First, Laurell and Eriksson reported an association of chronic airflow obstruction and emphysema with deficiency of serum α1-antitrypsin (α1-AT), the inhibitor of the serine proteinase neutrophil elastase (NE)(1). Second, Gross et al. developed the first reproducible model of emphysema, in which they injected the plant protease papain into the lungs of experimental animals (2). Together these two observations indicated that emphysema could be induced by proteolytic injury to the lung ECM, and they led to the elastase/antielastase hypothesis for the pathogenesis of emphysema. Prior to this time, mechanical explanations for emphysema dominated, although, as early as 1905, Opie had suggested that enzymes and antienzymes determined the risk of emphysema (3). Another largely forgotten hypothesis was Liebow’s vascular atrophy model for emphysema, proposed in the 1950s (4). In this issue of the JCI, Tuder and colleagues (5) revive this hypothesis armed with modern concepts of endothelial cell biology and cell death.

In order to appreciate the novelty of the findings presented by Tuder and colleagues.(5), one must understand how the elastase/antielastase hypothesis has evolved over the last 35 years. It is generally accepted that chronic exposure to cigarette smoke leads to recruitment of inflammatory cells into the terminal airspaces of the lung, where they release elastolytic proteinases in excess of inhibitors in local microenvironments, damaging the ECM of the lung. Ineffective repair of alveoli and elastic fibers and perhaps other ECM components results in airspace enlargement that defines pulmonary emphysema. We continue to struggle to determine the contribution of small airway changes and airspace enlargement to loss of lung function in COPD. Within this general framework, research has concentrated on which inflammatory cells and proteinases are most relevant. Macrophages predominate in the lungs of smokers, but neutrophils and T cells also accumulate in COPD. The importance of NE in the pathogenesis of emphysema associated with α1-AT deficiency has led the field to assume that this proteinase plays a similar role in more common forms of emphysema. However, work in transgenic and gene-targeted mouse models of the disease suggests that macrophage MMPs may also be important. Thus, mice deficient in macrophage elastase (MMP-12) fail to develop emphysema when exposed to long-term cigarette smoke (6), and overexpression of the interstitial collagenase MMP-1 in the lungs of transgenic mice also leads to airspace enlargement (7). Whether the latter phenotype reflects an event during the pathogenesis of emphysema or merely represents a developmental abnormality, this finding highlights the potential importance of matrix components other than elastin. Clearly, when