gastrin-releasing-peptide and Pulmonary-Fibrosis

Radiation-induced pulmonary fibrosis (RTPF) is a progressive, serious condition in many subjects treated for thoracic malignancies or after accidental nuclear exposure. No biomarker exists for identifying the irradiated subjects most susceptible to pulmonary fibrosis (PF). Previously, we determined that gastrin-releasing peptide (GRP) was elevated within days after birth in newborns exposed to hyperoxia who later developed chronic lung disease. The goal of the current study was to test whether radiation (RT) exposure triggers GRP release in mice and whether this contributes to RTPF in vivo. We determined urine GRP levels and lung GRP immunostaining in mice 0 to 24 after post-thoracic RT (15 Gy). Urine GRP levels were significantly elevated between 24 hours post-RT; GRP-blocking monoclonal antibody 2A11, given minutes post-RT, abrogated urine GRP levels by 6 to 12 hours and also altered phosphoprotein signaling pathways at 24 hours post-RT. Strong extracellular GRP immunostaining was observed in lung at 6 hours post-RT. Mice given one dose of GRP monoclonal antibody 2A11 24 hours post-RT had significantly reduced myofibroblast accumulation and collagen deposition 15 weeks later, indicating protection against lung fibrosis. Therefore, elevation of urine GRP could be predictive of RTPF development. In addition, transient GRP blockade could mitigate PF in normal lung after therapeutic or accidental RT exposure.

Topics: Animals; Female; Gamma Rays; Gastrin-Releasing Peptide; Mice; Phosphoproteins; Pulmonary Fibrosis; Radiation Injuries

Bombesin-like peptides promote fetal lung development. Normally, levels of mammalian bombesin (gastrin-releasing peptide [GRP]) drop postnatally, but these levels are elevated in newborns that develop bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by arrested alveolarization. In premature baboons with BPD, antibombesin antibodies reduce lung injury and promote alveolarization.. The present study tests whether exogenous bombesin or GRP given perinatally alters alveolar development in newborn mice.. Mice were given peptides intraperitoneally twice daily on Postnatal Days 1-3. On Day 14 lungs were inflation-fixed for histopathologic analyses of alveolarization.. Bombesin had multiple effects on Day 14 lung, when alveolarization was about half complete. First, bombesin induced alveolar myofibroblast proliferation and increased alveolar wall thickness compared with saline-treated control animals. Second, bombesin diminished alveolarization in C57BL/6 (but not Swiss-Webster) mice. We used receptor-null mice to explore which receptors might mediate these effects. Compared with wild-type littermates, bombesin-treated GRP receptor (GRPR)-null mice had increased interstitial fibrosis but reduced defects in alveolarization. Neuromedin B (NMB) receptor-null and bombesin receptor subtype 3-null mice had the same responses as their wild-type littermates. GRP had the same effects as bombesin, whereas neither NMB nor a synthetic bombesin receptor type 3 ligand had any effect. All effects of GRP were abrogated in GRPR-null mice.. Bombesin/GRP can induce features of BPD, including interstitial fibrosis and diminished alveolarization. GRPR appears to mediate all effects of GRP, but only part of the bombesin effect on alveolarization, suggesting that novel receptors may mediate some effects of bombesin in newborn lung.

Topics: Actins; Animals; Animals, Newborn; Bombesin; Cell Proliferation; Fibroblasts; Gastrin-Releasing Peptide; Gastrointestinal Agents; Injections, Intraperitoneal; Ligands; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurokinin B; Neurotransmitter Agents; Proliferating Cell Nuclear Antigen; Pulmonary Alveoli; Pulmonary Fibrosis; Receptors, Bombesin

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

Bronchial endocrine cells containing gastrin-releasing peptide (GRP), a mammalian analog of bombesin, and adrenocorticotropic hormone (ACTH) were immunohistochemically localized in paraffin sections of normal and pathologic human lungs. GRP-containing cells were present in fetal bronchi at the 12th gestational week and in "neuroepithelial bodies" about the time of delivery. In normal adult lungs, a few isolated GRP-containing cells were present in bronchial and bronchiolar mucosa. In bronchiectatic or fibrotic lungs, small clusters of GRP-containing cells were occasionally noted in basal bronchial mucosa. Pronounced GRP cell hyperplasia often was observed in ectatic bronchioles of lungs with tumorlet. Cells of pulmonary tumorlets mostly showed GRP immunoreactivity. Two bronchial carcinoids exhibited a moderate number of GRP-containing cells. Three of four small cell carcinomas, intermediate cell type could be designated "GRPomas" from the number of GRP-containing cells present. In four of 11 small cell carcinomas, oat cell type, GRP immunoreactivity was infrequently recognized. Immunoabsorption tests indicated that GRP immunoreactivity in lungs would mainly fall under the C-terminal fragment rather than the whole sequence of GRP. Bombesin immunoreactivity in human lungs should be attributed to GRP or GRP-like molecules, since no bombesin immunoreactants were identified with bombesin antiserum which shows no cross-reactivity to porcine GRP. ACTH-containing cells, also reactive to beta-endorphin antiserum, were absent from normal fetal or adult lungs but did accompany GRP-containing cells occasionally in ectatic non-neoplastic bronchioles, always in tumorlet cells, and often in endocrine lung tumors, although the cells containing GRP and ACTH were not identical. The significance of GRP in the physiology and pathophysiology of the lung is discussed, and the necessity of reevaluation of "ectopic" ACTH production in lung neoplasms is proposed.

Topics: Adrenocorticotropic Hormone; Adult; Antibodies; Bombesin; Bronchi; Carcinoid Tumor; Carcinoma, Small Cell; Fetus; Gastrin-Releasing Peptide; Histocytochemistry; Humans; Immune Sera; Immunochemistry; Immunoenzyme Techniques; Infant; Infant, Newborn; Lung; Lung Neoplasms; Peptides; Pulmonary Fibrosis; Substance P

Formalin-fixed paraffin-embedded sections of fetal and adult human lungs were examined for the localization of gastrin releasing peptide (GRP) and calcitonin (CT) in bronchial endocrine-type cells with the indirect immunoperoxidase method. In fetal lungs, the appearance of CT was much later than that of GRP, and CT-containing cells were less frequent than GRP-containing cells which, in later fetal life, formed "neuroepithelial bodies (NEB)". NEB revealed little CT immunoreactivity. The serial section technique demonstrated that all CT immunoreactants in fetal and neonatal lungs were present within GRP-containing cells. An increase of CT immunoreactivity in GRP-containing cells was observed in perinatal lungs. The lung of a neonate who died of hyaline membrane disease contained the most abundant CT immunoreactants. In adult lungs, CT immunoreactivity was identified in some GRP-containing cells but cells containing only GRP or CT were also present. Cells containing both hormones occasionally formed hyperplastic foci in the bronchi of fibrotic lungs. Most cells of pulmonary tumorlets consistently showed GRP immunoreactivity, but the number of CT immunoreactive cells in them varied greatly.

Topics: Adult; Age Factors; Aged; Bronchi; Calcitonin; Fetus; Gastrin-Releasing Peptide; Histocytochemistry; Humans; Hyaline Membrane Disease; Immunoenzyme Techniques; Infant; Infant, Newborn; Middle Aged; Peptides; Pulmonary Fibrosis