vasoactive-intestinal-peptide and Pulmonary-Fibrosis

Vasoactive intestinal peptide (VIP) is an intrapulmonary neuropeptide with multi-function, including anti-fibrosis. However, the exact role of VIP in pulmonary fibrosis has not been documented. Here, we investigated the protective effect of VIP against pulmonary fibrosis in a murine model induced by bleomycin (BLM). We found that the overexpression of VIP mediated by the adenoviral vector significantly attenuated the lung tissue destruction, reduced the deposition of the extracellular matrix, and inhibited the expression of alpha-smooth muscle actin (α-SMA) in the lungs of mice received BLM. Mechanismly, we found that VIP significantly suppressed the transforming growth factor-beta 1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) and inhibited the matrix-producing ability of alveolar epithelial cells in vitro. Furthermore, we found that TGF-β1 depressed the autophagy and an autophagy inductor partly reversed the TGF-β1-induced EMT in alveolar epithelial cells. The impaired autophagy was also observed in the lungs of BLM-treated mice, which was restored by VIP treatment. And VIP treatment enhanced autophagy in TGF-β1-stimulated alveolar epithelial cells, contributing to its anti-EMT effect. In summary, our data, for the first time, show that VIP attenuates BLM-induced pulmonary fibrosis in mice with anti-EMT effect through restoring autophagy in alveolar epithelial cells. This study provides a possibility that inhaled long-acting VIP may be an anti-fibrotic drug in the treatment of pulmonary fibrosis.

Topics: Alveolar Epithelial Cells; Animals; Antibiotics, Antineoplastic; Autophagy; Bleomycin; Epithelial-Mesenchymal Transition; Mice; Pulmonary Fibrosis; Vasoactive Intestinal Peptide; Vasodilator Agents

The neuropeptide gastrin releasing peptide (GRP) is present in the lung, and functions as a modulator of tissue growth and repair in fibrotic processes, or as a modulator of cell movement and differentiation in various inflammatory processes, including granulomatous ones. In idiopathic pulmonary fibrosis (IPF), changes in the bronchoalveolar lavage (BAL) content of GRP can be expected. We measured GRP-like immunoreactive substances (GRP-IS) and another neuropeptide, vasoactive intestinal peptide (VIP)-IS in BAL by enzyme immunoassay. Our results showed a decrease in BAL GRP-IS in patients with IPF (26.5 +/- 5.5 pg.mg-1 protein) and sarcoidosis (35.9 +/- 9.2 pg.mg-1), compared to healthy nonsmokers (63.4 +/- 9.0 pg.mg-1). When data were expressed as pg.ml-1 BAL fluid recovered, a decrease was only seen in IPF, not in sarcoidosis. The levels of VIP-IS in BAL were not different between the groups studied. Increased protein levels in BAL had no correlation with the levels of GRP-IS or VIP-IS in BAL. Furthermore, BAL neutrophil percentages had no correlation with the levels of GRP-IS in BAL of patients with IPF. Using reversed phase high performance liquid chromatography (HPLC), several kinds of GRP-IS were detected in BAL. These findings suggest that the decreased level of GRP-IS in BAL may reflect a loss of GRP-producing cells due to chronic lung injury and fibrosis in patients with IPF.

Topics: Adult; Bronchoalveolar Lavage Fluid; Chromatography, High Pressure Liquid; Female; Gastrin-Releasing Peptide; Gastrointestinal Hormones; Humans; Immunoenzyme Techniques; Lung Diseases; Male; Middle Aged; Peptides; Pulmonary Fibrosis; Sarcoidosis; Smoking; Vasoactive Intestinal Peptide

The purpose of this study was to determine if asbestos-induced pulmonary fibrosis in the rat can affect the levels of autacoids and peptides in freshly isolated lung cells. Lung fibrosis was experimentally induced in rats by a single intratracheal instillation of 5 mg UICC Canadian chrysotile B fibers. Isolated lung cells were prepared from normal and from asbestos-exposed rats. These cells were also fractionated on bovine serum albumin (BSA) gradients. The contents of serotonin (5-HT), histamine (HIST), vasoactive intestinal peptide (VIP), and bombesin (BN) were measured in isolated total cell preparations as well as in density-fractionated cell populations from normal and from asbestos-exposed rats. Analysis of total lung cell preparation showed the presence of heterogeneous populations in normal rat lung. After asbestos exposure, there were significant changes in these cell populations as evidenced by significant increases in lymphocyte and mast cell numbers. In addition, increased levels of 5-HT, HIST, and VIP were observed in isolated lung cells obtained from rats exposed to asbestos 1, 3, and 6 months after instillation. BN content was unchanged 3 months after treatment, but was significantly increased at the 6 month-interval, suggesting a different pattern of response for this neuropeptide. Density fractionation of various cell populations further showed selective changes in specific cell fractions of lung after asbestos exposure. At 6 months, increased levels of 5-HT, HIST, and VIP were associated with cell fraction 7, whereas changes in BN content were found in cell fractions 2 and 3. Similarly, there was a significant increase of mast cells in fraction 7 at the 6-month interval.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Asbestosis; Autacoids; Bombesin; Disease Models, Animal; Histamine; Lung; Male; Microscopy, Electron; Neuropeptides; Pulmonary Fibrosis; Rats; Rats, Inbred Strains; Serotonin; Specific Pathogen-Free Organisms; Time Factors; Vasoactive Intestinal Peptide

The pulmonary levels of immunoreactive bombesin in normal rat lungs and rat lungs exposed to asbestos were determined. Experimental asbestosis was induced in rats by a single intratracheal injection of 5 mg or 10 mg UICC standard Canadian Chrysotile B while sham-operated control rats received only the saline carrier. At 1, 3, 6, and 9 months following instillation, 5 animals of each group were sacrificed and the lungs removed. A section was kept for morphologic analysis, while the remaining portion was submitted to acid extraction and later measured for bombesin content by radioimmunoassay (RIA). The Chrysotile B-exposed tissues displayed the characteristic features typical of the fibrotic state associated with asbestosis one month following exposure and thereafter. The pulmonary bombesinlike immunoreactivity ranged from 4.5-7.5 pmoles/g tissue in normal rat lung, and these levels remained unchanged at 1 and 3 months after asbestos exposure. However at 6 and 9 months, significant increases ranging between 2 and 2.5 fold were observed. The initial increases in bombesin levels occurred at a later time (6 months) than those already observed for vasoactive intestinal peptide (VIP) (3 months). However, VIP levels plateaued at 9 months, while those of bombesin were still increasing. High-pressure liquid chromatography (HPLC) coupled with RIA demonstrates the presence of two bombesin-immunoreactive peaks in normal rat lung, the major one coeluting with the mammalian bombesinlike peptide gastrin-releasing peptide (GRP) and the other one being presumably a C-terminal portion of GRP. These data indicate that immunoreactive bombesin and VIP are selectively increased at different times following asbestos instillation and that these changes occur after the onset of fibrosis and the appearance of well-defined fibrotic lesions.

Topics: Animals; Asbestosis; Bombesin; Chromatography, High Pressure Liquid; Lung; Male; Peptides; Pulmonary Fibrosis; Radioimmunoassay; Rats; Rats, Inbred Strains; Reference Values; Vasoactive Intestinal Peptide