RETRACTED: Gastrin-releasing peptide blockade as a broad-spectrum anti-inflammatory therapy for asthma

Abstract

Gastrin-releasing peptide (GRP) is synthesized by pulmonary neuroendocrine cells in inflammatory lung diseases, such as bronchopulmonary dysplasia (BPD). Many BPD infants develop asthma, a serious disorder of intermittent airway obstruction. Despite extensive research, early mechanisms of asthma remain controversial. The incidence of asthma is growing, now affecting >300 million people worldwide. To test the hypothesis that GRP mediates asthma, we used two murine models: ozone exposure for air pollution-induced airway hyperreactivity (AHR), and ovalbumin (OVA)-induced allergic airway disease. BALB/c mice were given small molecule GRP blocking agent 77427, or GRP blocking antibody 2A11, before exposure to ozone or OVA challenge. In both models, GRP blockade abrogated AHR and bronchoalveolar lavage (BAL) macrophages and granulocytes, and decreased BAL cytokines implicated in asthma, including those typically derived from Th1 (e.g., IL-2, TNFα), Th2 (e.g., IL-5, IL-13), Th17 (IL-17), macrophages (e.g., MCP-1, IL-1), and neutrophils (KC = IL-8). Dexamethasone generally had smaller effects on all parameters. Macrophages, T cells, and neutrophils express GRP receptor (GRPR). GRP blockade diminished serine phosphorylation of GRPR with ozone or OVA. Thus, GRP mediates AHR and airway inflammation in mice, suggesting that GRP blockade is promising as a broad-spectrum therapeutic approach to treat and/or prevent asthma in humans.

Gastrin-releasing peptide receptor (GRPR) mediates chemotaxis in neutrophils

“…Our results also provide a unique candidate mechanism for the antiinflammatory effect of the GRPR antagonist RC-3095 in models of arthritis (9) and sepsis (10). We can also extend our model to explain the proinflammatory effect of GRP, because a GRP blocking agent effectively prevented asthma exacerbation in animal models (12). The effective role of GRP in inflammation has not been characterized.…”

“…It has recently been demonstrated that neutrophils express GRPR (12). Chemokines (17) and leukotrienes (21) and molecules released by damaged tissues (22,23) act as chemoattractants, acting directly on neutrophils to induce migration.…”

“…Interestingly, GRPR has been found to be expressed in immune cells (12). Inflammation is a protective immune response initiated by exposure of innate immune cells to molecular patterns that signal infection or injury (13), and the migration of neutrophils to sites of inflammation can promote tissue damage (14), although it is also critical for healing of the affected areas (15).…”

DIPNECH: Association Between Histopathology and Clinical Presentation

“…GRP has been shown to directly induce smooth muscle constriction in animal models [10][11][12]. Furthermore, GRP blockade has been able to prevent airway hyper-reactivity and airway inflammation in two distinct mouse models of asthma [13]. Keeping these data into account, one might speculate that GRP-induced bronchoconstriction be a second mechanism, besides constrictive bronchiolitis, through which patients with DIPNECH may develop symptoms.…”

Neural processing of itch

“…Thus, expression of GRP in DRG neurons may reflect a peripheral role of GRP in itch. Moreover, the GRP receptor (GRPR) is expressed in immune cells, such as macrophages, T-cells and neutrophils, and contributes to development of inflammatory diseases (Zhou et al, 2011, Czepielewski et al, 2012). GRP might play a key role in transmission of itch signaling as well as modulating neuroimmune interactions.…”