gastrin-releasing-peptide and Lung-Diseases

Sepsis is a complex, multifactorial syndrome that can develop into conditions of different severity, described as septic shock or severe sepsis. In spite of the great progress in understanding the mechanisms involved in the pathogenesis and management of sepsis, only a few therapeutic strategies were able to show a decrease in the mortality from septic shock. Although sepsis consists on a systemic inflammatory response, the anti-inflammatory therapies have failed to improve the outcome of critically ill patients. Here the role of gastrin-releasing peptide in immune processes is reviewed and the data that have prompted the recent patent for GRP receptor antagonists RC-3095 as a therapeutic agent on inflammatory conditions are described.

Topics: Animals; Bombesin; Gastrin-Releasing Peptide; Humans; Immune System; Lung Diseases; Patents as Topic; Receptors, Bombesin; Sepsis

The proliferation of the bronchial epithelium and tumors associated with this tissue is controlled by various growth factors. The main factor is Gastrin Releasing Peptide (GRP), the human counterpart of the amphibian bombesin. These neuropeptides also act as neuromediators and gut hormones. All peptides of this family share a conserved C terminal sequence which is required for biological activity. The determination of this sequence has provided the basis for the design of specific agonist and antagonist peptides and for the generation of monoclonal antibodies (Mab). GRP interacts with a receptor coupled to a G protein and the signalling process leads to the activation of phospholipase C and kinases, and the mobilization of calcium. GRP promotes the proliferation of foetal and adult bronchial epithelium and of small cell lung cancer (SCLC) cells. GRP is also an autocrine growth factor for some SCLC cell lines. The growth of these lines is reduced in vitro and in vivo by MAb and specific antagonists. Hyperplasia of GRP producing cells has been shown in various lung diseases in adults and children. Pharmacological data on GRP suggest that its antagonists could be used in the treatment of SCLC (in addition to chemotherapy) and of interstitial lung disease. The cloning of the GRP receptor should facilitate the design of specific and potent antagonists of the peptide.

Topics: Adult; Bombesin; Fetus; Gastrin-Releasing Peptide; Gastrins; Growth Substances; Humans; Lung; Lung Diseases; Peptides

Topics: Amino Acid Sequence; Animals; Central Nervous System; Digestive System; Gastrin-Releasing Peptide; Gene Expression Regulation; Humans; Lung; Lung Diseases; Molecular Sequence Data; Peptides; Receptors, Bombesin; Receptors, Neurotransmitter; Thyroid Gland; Thyroid Neoplasms

Gastrin-releasing peptide (GRP) is produced by pulmonary neuroendocrine cells (PNECs), with highest numbers of GRP-positive cells present in fetal lung. Normally GRP-positive PNECs are relatively infrequent after birth, but PNEC hyperplasia is frequently associated with chronic lung diseases. To address the hypothesis that GRP mediates chronic lung injury, we present the cumulative evidence implicating GRP in bronchopulmonary dysplasia (BPD), the chronic lung disease of premature infants who survive acute respiratory distress syndrome. The availability of well-characterized animal models of BPD was a critical tool for demonstrating that GRP plays a direct role in the early pathogenesis of this disease. Potential mechanisms by which GRP contributes to injury are analyzed, with the main focus on innate immunity. Autoreactive T cells may contribute to lung injury late in the course of disease. A working model is proposed with GRP triggering multiple cell types in both the innate and adaptive immune systems, promoting cascades culminating in chronic lung disease. These observations represent a paradigm shift in the understanding of the early pathogenesis of BPD, and suggest that GRP blockade could be a novel treatment to prevent this lung disease in premature infants.

Topics: Animals; Bombesin; Bronchopulmonary Dysplasia; Gastrin-Releasing Peptide; Humans; Immune System Phenomena; Immunity, Innate; Infant, Newborn; Lung Diseases; Models, Biological; T-Lymphocytes

Topics: Adult; Fetal Organ Maturity; Gastrin-Releasing Peptide; Humans; Infant, Newborn; Lung; Lung Diseases; Receptors, Bombesin; Respiratory Distress Syndrome

It is not clear whether there is any association between metaplasia of the bronchial epithelium and changes in the distribution of neuroendocrine cells. This study examined, by immunohistological techniques, the distribution of neuroendocrine cells and juxtamucoscal nerve fibres in bronchial biopsies showing metaplastic changes.. Bronchial biopsies from 12 subjects with epithelial metaplasia associated with bronchiectasis and diffuse pulmonary fibrosis were examined by conventional light microscopy and immunohistological techniques for protein gene product 9.5 (PGP), chromogranin A and B (CAB), serotonin, vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), calcitonin (CT), and gastrin releasing peptide (GRP).. Regions of non-metaplastic epithelium contained numerous PGP and serotonin immunoreactive cells. Sub-populations of these cells displayed CAB, CGRP, CT, and GRP immunoreactivity. Metaplastic epithelium contained only a few weakly stained PGP, serotonin, CAB, GRP, CT and CGRP immunoreactive cells in six cases. Metaplastic epithelium was characterised by a high number of CAB-containing cells in six cases and in these biopsies prominent PGP-containing nerve bundles were seen in the subepithelial layer beneath the metaplastic epithelium.. The distribution patterns of neuroendocrine cells and neuronal elements vary between areas of normal and metaplastic epithelium and within areas of metaplastic epithelium. Neuronal hyperplasia was associated with an increase in the number of CAB-containing cells within the metaplastic epithelium.

Topics: Adult; Aged; Bronchi; Calcitonin; Calcitonin Gene-Related Peptide; Chromogranin A; Chromogranins; Chronic Disease; Gastrin-Releasing Peptide; Gastrins; Humans; Immunohistochemistry; Lung Diseases; Middle Aged; Mucous Membrane; Neurosecretory Systems; Peptides; Serotonin; Substance P; Thiolester Hydrolases; Ubiquitin Thiolesterase

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