A role for peptidergic nerves in the adult respiratory distress syndrome (ARDS) was examined by radioimmunochemically quantifying neuropeptides in pulmonary edema (PE) fluids from seven patients with ARDS and six patients with PE from congestive heart failure (CHF). The PE fluid mean concentrations of substance P (SP) and gastrin-releasing peptide (GRP) were significantly higher in ARDS (0.59 ±0.29SD and 0.10=0.03 nM, respectively,P < 0.001 for both) than in CHF (0.19±0.08 and 0.04±0.01), whereas no difference was detected between the mean levels of vasoacti ve intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) in the two forms of PE. Mean alveolar fluid concentration of SP was 8.7 nM (range 2.1−20.5 nM,N=4) in sheep with acute lung injury from intravenousPseudomonas aeruginosa, but was undetectable in sheep with balloon-induced high left atrial pressure simulating CHF (N=2) or control sheep (N=2). Pulmonary lymphatic clearance of SP, which reflected the rate of generation of SP in the lungs, attained a maximum of 25–95 pmol/h in sheep givenP. aeruginosa intravenously, but was detected in only one of four control sheep at a lower level. Some pulmonary neuropeptides thus are released locally by acute lung injury and may contribute to endothelial and/or epithelial abnormalities underlying the altered capillary-alveolar permeability in ARDS.