The pulmonary endothelin (ET) system has been implicated in the pathogenesis of chronic lung diseases such as pulmonary hypertension, asthma, chronic obstructive lung disease, idiopathic pulmonary fibrosis, and bronchiolitis obliterans. However, the etiologic role of ET-1 in these diseases has not yet been established. We recently demonstrated that ET-1 transgenic mice, generated using the human prepro-ET-1 expression cassette including the cis-acting transcriptional regulatory elements, had predominant transgene expression in lung, brain, and kidney. We used these mice in the present study to analyze the pathophysiologic consequences of long-term pulmonary overexpression of ET-1. We found that ET-1 overexpression in the lungs did not result in significant pulmonary hypertension, but did result in development of a progressive pulmonary fibrosis and recruitment of inflammatory cells (predominantly CD4-positive cells). Our study provides evidence that a long-term activated pulmonary ET system, without any other stimuli, produces chronic lymphocytic inflammation and lung fibrosis. This suggests that overexpression of ET-1 may be a central event in the pathogenesis of lung diseases associated with fibrosis and chronic inflammation, such as pulmonary fibrosis and bronchiolitis.

Periumbilical necrotizing fasciitis (PNF) in the newborn is an invasive bacterial infection of the abdominal wall with a fulminant course and a high mortality rate. Little is known about the etiology, risk factors and microbiology of the disease. 18 patients with periumbilical necrotizing fasciitis were included in this retrospective study and were compared with 50 patients with omphalitis over a 6-year period, between 1992 and 1998. This represents the largest reported study. The children with periumbilical necrotizing fasciitis presented at a younger age compared to the omphalitis group (8.4 days vs. 9.1 days) and had a shorter clinical history (1.9 days vs. 2.8 days), suggesting that PNF is not a mere sequela of omphalitis but has distinctive underlying causes. None of our patients in the omphalitis group had a progression of the disease towards necrotizing fasciitis. The microbial spectrum of cultures obtained in patients with PNF consisted of mixed anaerobes and aerobes in 55%, and mixed aerobes in 36% of cases. Early aggressive therapy, including elective endotracheal intubation, immediate surgical debridement of the abdominal wall, antibiotics and supportive measurements resulted in a survival rate of 56%. Far from being satisfactory, this is nevertheless higher than the 12.5% to 45% survival rate quoted in previous publications.