Prostaglandin E (PGE), a cyclooxygenase metabolite normally present in high concentrations in respiratory epithelial lining fluid (ELF), is capable of suppressing mesenchymal cell proliferation mediated by polypeptide-derived growth factors. Although PGE is normally abundant in respiratory ELF, PGE levels in ELF of individuals with idiopathic pulmonary fibrosis (IPF), a fibrotic lung disorder characterized by intraalveolar mesenchymal cell accumulation and fibrosis, were found to be 50% lower than normal (p less than 0.01): that is, a relative PGE "deficiency" in ELF may enhance intraalveolar mesenchymal cell proliferation in IPF. With this background, it is rational to consider augmenting PGE levels in ELF as a future therapy for IPF. Since systemic administration of PGE is associated with significant adverse effects, in vitro and experimental animal studies were carried out to evaluate whether aerosol PGE administration could augment ELF PGE levels. Greater than 50% of a solution of PGE1 could be placed in droplets less than 3 microns mass median aerodynamic diameter without loss of function. Aerosolization of PGE1 to sheep (n = 14) resulted in a marked augmentation of ELF PGE1 levels (preaerosol 20 +/- 7 nM, 30 min postaerosol 1,150 +/- 210 nM; p less than 0.0 to 0.1). ELF PGE1 levels remained elevated for up to 2 h (p less than 0.05 compared with baseline) and returned to baseline by 3 h (p greater than 0.2). Lung interstitial fluid (lymph) PGE1 levels increased slightly, but to levels far less than ELF levels (preaerosol 7 +/- 1 nM, 30 min postaerosol 13 +/- 2 nM; p less than 0.01), and plasma PGE1 levels did not change (p greater than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

To clarify the role of thrombin in fibroblast growth and the development of pulmonary fibrosis in bleomycin-induced interstitial lung disease, we examined the relationship of thrombin activity to fibroblast growth-stimulating activity (FGA) in bronchoalveolar lavage (BAL) fluid from bleomycin-treated rats. Male Wistar rats were given a single intratracheal injection of bleomycin, BAL was performed 2, 6, and 15 days later, and the BAL fluid was assayed for thrombin activity and FGA. Higher FGA than the control value was detected in the BAL fluid from rats on day 6 after bleomycin administration. In bleomycin-treated rats, thrombin activity in the BAL fluid was significantly elevated on day 2 and maximal on day 6. The FGA of the BAL fluid from bleomycin-treated rats on day 6 was significantly decreased by its treatment with various thrombin inhibitors, such as alpha 1-protease inhibitor, antithrombin III, hirudin, and MD-805. In our assay, purified rat thrombin also showed FGA in vitro, and its FGA was inhibited by the same concentrations of these thrombin inhibitors as those inhibiting the activity in the BAL fluid. On ammonium sulfate fractionation, most of the thrombin activity was recovered in the fraction of 35 to 50% saturation in which most of the FGA was detected. These results suggest that the FGA of the BAL fluid from bleomycin-treated rats was at least partly due to thrombin is responsible, at least in part, for fibroblast growth and pulmonary fibrosis in bleomycin-induced interstitial lung disease.

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This study was designed to clarify the contributions of specific neutrophil chemotactic factors (NCF) in neutrophil accumulation in the human respiratory tract associated with various diseases. The activity and characteristics of the NCF in the bronchoalveolar lavage (BAL) fluid and culture media of alveolar macrophages obtained from normal volunteers, control patients, patients with chronic airway diseases (CAD) and patients with idiopathic pulmonary fibrosis (IPF) were examined. The BAL fluid from normal volunteers contained NCF comparable with the chemotactic factors interleukin-8 (IL-8) and leukotriene B4 (LTB4). Analysis of the biochemical characteristics of NCF released from alveolar macrophages suggests that they are derived from alveolar macrophages. The NCF activities in BAL fluids from patients with CAD and IPF were higher than those in BAL fluids from normal volunteers and control patients. Biochemical analysis demonstrated that several kinds of NCF, including those derived from the complement component C5 and alveolar macrophages, were present in the BAL fluid from patients with CAD and respiratory infections. The especially marked increase of C5-derived NCF indicate their importance in neutrophil accumulation in the respiratory tract of patients with CAD. Alveolar macrophages released different types of NCF after different lengths of culture periods (4 h and 24 h). Alveolar macrophages from patients with IPF released larger amounts of NCF than alveolar macrophages from normal volunteers, indicating the importance of alveolar-macrophage-derived NCF as well as C5-derived NCF in neutrophil accumulation in the respiratory tract of patients with IPF. These results suggest that various types of NCF increase in response to different disease states of the respiratory tract and serve to regulate the accumulation of neutrophils.

Cyclooxygenase metabolites of arachidonic acid are thought to play an important role in the regulation of diverse physiological functions in the lung. Although the concentration of these metabolites required to have effects is several orders of magnitude greater than the concentration of these mediators in the blood, it has been postulated that local concentrations within tissues are much higher. In a direct test of this hypothesis, the concentrations of the cyclooxygenase products of arachidonic acid including prostaglandin (PG) E, PGF2 alpha, 6-keto-PGF1 alpha, and thromboxane B2, were measured in a specialized tissue compartment, the epithelial surface of the lower respiratory tract. The concentration of these mediators within this compartment was 50- to 80-fold greater than concurrent blood levels and are sufficient to likely have physiological effects. Thus the epithelial surface of the lower respiratory tract represents a specialized compartment with high local levels of cyclooxygenase products of arachidonic acid.