Vascular endothelial growth factor and the pathogenesis of emphysema

The lungs are subject to many diseases, particularly chronic obstructive pulmonary disease (COPD) and asthma, which are the most common in North America. Although very different in pathology and clinical features, they share a common element of obstruction to bronchial airflow as their physiological hallmark. Chronic obstructive pulmonary disease, a syndrome of variable phenotype, is mostly caused by inhaled cigarette smoke. Over time, alveolar destruction results in emphysema, and chronic bronchial inflammation leads to chronic bronchitis—which is why COPD is often called “emphysema and chronic bronchitis.” For decades, medical students have been taught that the alveolar destruction in emphysema is due to an excess of proteases (over antiproteases), which digest the parenchymal connective tissue, altering alveolar architecture to cause the lesion. Somehow, inhaled cigarette smoke causes this imbalance. Students have also been taught that inflammatory components in cigarette smoke chronically irritate the airway epithelium, leading to airway remodeling and excessive mucus production. Both processes lead to airflow obstruction— emphysema by increasing dynamic compression from reduced elastic recoil, and chronic bronchitis because of airway structural changes and mucus plugging that reduce airway lumen size. Asthma, on the other hand, is considered an airway disease, albeit one in which there is also widespread inflammation. Although airway remodeling and excess/altered mucus production are also seen in asthma, this disease, which occurs in the absence of cigarette smoke inhalation, has for years been distinguished from chronic bronchitis by the finding of increased airway smooth muscle responsiveness to a host of stimuli. This results in bronchoconstriction that can often be reversed quickly, at least in part, with beta-adrenergic agonists. We are now reminded that these classic views of COPD and asthma are possibly too simple and that totally different pathogenetic pathways may contribute to both COPD and asthma. In this issue of the Journal, Kanazawa et al. present data associating altered expression of vascular endothelial growth factor (VEGF) with functional state in both syndromes (1). As its name implies, VEGF is predominantly an endothelial mitogen, which, since its discovery as vascular permeability factor some 20 years ago (2), has been found to be an important growth factor during development. In mice, knockout of even one allele leads to embryonic death in utero (3), owing to failure of cardiovascular development. Deletion or inhibition of VEGF in specific tissues in adult mice, such as skeletal muscle, has had notable effects, mainly gross reduction in capillarity with tissue cell apoptosis (4). There has been much study of the potential value of VEGF inhibition in cancer therapy, and the results have been promising (5). The logic is straightforward in each case: tissue growth and survival (normal or cancerous) depend on its vascular supply, and vascular supply depends in turn on VEGF. It should thus come as no surprise that if VEGF is critical to tissue vascularity and tissue survival, reduction of VEGF in the lungs, an organ that normally has high levels of VEGF, may result in parenchymal loss. This would possibly lead to a phenotype that looks like emphysema, in which the histological hallmark is alveolar wall destruction leading to fewer but larger alveoli. Indeed, Kasahara et al. (6) showed this by blocking the VEGF receptor VEGFR-2 (also known as KDR, Flk) in rats. Parenchymal cell apoptosis occurred, and alveolar spaces were enlarged. Kasahara et al. (7) went on to show that in human lung tissue, VEGF levels were reduced and apoptosis was evident in patients with emphysema as compared with normal patients and those without emphysema who smoked. These results have also been observed in adult mice depleted of pulmonary VEGF by a Cre/ LoxP-targeted deletion technique (8). In these mice, histological and mechanical evidence of emphysema developed within a few weeks. What Kanazawa et al. have provided here is further evidence that VEGF may be involved in the pathogenesis of emphysema (1). They have extended these ideas to chronic bronchitis and asthma. They examined VEGF levels in the induced sputum of such patients and found a remarkably close correlation with both spirometry (measured as forced expiratory volume in 1 second [FEV1]) and diffusing capacity of lung for carbon monoxide (DLCO). These two functional parameters are widely used as quantitative indicators of severity in patients with airways obstruction. In emphysema patients, they found that the lower the FEV1 or DLCO, the lower the VEGF level in sputum, which is directionally consistent with what Kasahara et al. have reported (7). In patients with chronic bronchitis, Kanazawa et al. found an equally strong correlation with FEV1, but in the opposite direction: the Am J Med. 2003;114:413– 414. From the Division of Physiology, Department of Medicine, University of California, San Diego, La Jolla, California. Requests for reprints should be addressed to Peter D. Wagner, MD, Division of Physiology, Department of Medicine, University of California, San Diego, 9500 Gilman Drive, MC 0623A, La Jolla, California 92093-0623, or pdwagner@ucsd.edu.