American Journal of Respiratory and Critical Care Medicine

Bombesin is a 14-amino acid bioactive peptide originally isolated from frog skin in 1971. With the use of antibodies to amphibian bombesin, bombesin-like immunoreactivity has been identified in mammalian brain, gut, and lung (1). During the last 30 years, several bombesin-like peptides have been characterized, including the gastrin-releasing peptide (GRP), neuromedin B, and phyllolitorins. These neuropeptides are secreted by neuronal and endocrine cells and function as neurotransmitters in the central nervous system and as regulators of numerous gastrointestinal functions, including the release of gastrointestinal hormones, stimulation of amylase secretion from the pancreas, and smooth muscle contraction. To date, three mammalian bombesin-like receptors have been cloned: GRP/bombesin-preferring receptor, neuromedin B receptor, and the orphan bombesin receptor subtype 3. These receptors are seven-transmembrane–spanning, G protein–coupled receptors primarily leading to the activation of multiple cell signaling pathways. Distinct distributions of bombesin receptor subtypes in the central nervous system as well as in peripheral organs suggest that these receptors may mediate different biological effects (1).

There is a growing body of experimental and clinical evidence that bombesin-like peptides play an important role in the normal lung development and in several pathologic conditions in the lung, such as bronchopulmonary dysplasia in premature infants and chronic inflammatory lung diseases, including lung cancer, cystic fibrosis, eosinophilic granuloma, and pulmonary hypertension. In the normal fetal lung, bombesin-like peptides promote branching morphogenesis. Furthermore, recent experimental work suggests that bombesin-like receptors may have different roles in lung development, with the GRP receptor being mostly involved in mesenchymal and epithelial cell proliferation, alveolar type II cell differentiation, and surfactant phospholipid production, thus arguing against simple functional redundancy within this gene family (2). Postnatally, bombesin-like peptides are critical mediators of the development of bronchopulmonary dysplasia (35), and are implicated in the pathophysiology of several other chronic lung inflammatory diseases (6), in part via the release of these peptides by hyperplasic pulmonary neuroendocrine cells.

In this issue of the Journal (pp. 84–90), Dal-Pizzol and colleagues (7) describe a new and important role for bombesin-like peptides in mediating acute lung damage resulting from sepsis. The administration of a selective GRP receptor antagonist, RC-3095, 6 hours after induction of peritonitis significantly improved survival in this clinically relevant model of sepsis-mediated acute lung injury. A second series of studies demonstrated that this selective GRP receptor antagonist also protected the lung against a locally administered injurious agent, Escherichia coli endotoxin. The final set of studies tested the hypothesis that inhibiting the GRP receptor on macrophages would decrease the release of proinflammatory mediators by these cells. The results indicated that inhibiting the GRP receptor at the surface of macrophages within 30 minutes, but not 2 hours, after exposure to endotoxin decreased the release of proinflammatory cytokines and nitric oxide by these cells. The results of this elegant set of studies are important for several reasons. First, these experiments demonstrate for the first time an important role for bombesin-like peptides in the pathogenesis of acute lung injury. Indeed, systemic and/or intrapulmonary released bacterial products activated the secretion of these neuropeptides, resulting in the amplification of the inflammatory response in the lung. Second, these studies established that immune cells, such as macrophages, can release bombesin-like peptides that positively modulate the release of proinflammatory mediators.

Despite the importance of the results in this study (7), several questions about the role of bombesin-like peptides in acute lung injury remain unanswered. First, are macrophages the only lung cells whose inflammatory response to bacterial products can be modulated by bombesin-like peptides? Second, do these neuropeptides act only as modulators of proinflammatory signaling pathways or are they themselves able to induce an inflammatory response? Third, are these peptides only released within the distal airspaces or are they also released systemically? The studies related to the role of bombesin-like peptides in the pathogenesis of bronchopulmonary dysplasia in premature infants may help to provide clues to answer the first of these questions. There is good clinical and experimental evidence for a role of pulmonary neuroendocrine cells in releasing bombesin-like peptides during the development of bronchopulmonary dysplasia. Furthermore, these neuropeptides have a positive feedback on the proliferation of these neuroendocrine cells in the lung, and the urine concentration of these peptides is predictive of the development of this devastating disease in premature children (35). These results suggest that cells other than macrophages, such as pulmonary neuroendocrine cells, could be involved in the release of bombesin-like peptides in acute lung injury from sepsis. This hypothesis is reinforced by the fact that proliferation of pulmonary neuroendocrine cells can occur within 4 to 24 hours after the onset of hypoxia (8) and that these cells release bombesin-like peptides and tachykinins in response to oxidants (9) or exposure to proinflammatory cytokines, such as tumor necrosis factor (TNF)-α (10). Interestingly, tachykinins, such as substance P, have recently been shown to participate to the development of pulmonary edema in acute lung injury by causing an exaggerated neurogenic inflammation mediated by the activation of the neurokinin receptor type 1 (11).

Data from the present study indicate that the activation of the GRP receptor positively modulates the in vitro expression of endotoxin-responsive genes by peritoneal macrophages. However, the authors did not determine whether bombesin-like peptides could directly induce the release of proinflammatory cytokines by these cells. Previously published studies have reported that these neuropeptides can activate the nuclear factor-κB and mitogen-activated protein kinase pathways in cancer cells (12, 13). Furthermore, neuropeptides added in vitro to white blood cells are able to stimulate the production of interleukin (IL)-1β, IL-6, and TNF-α (14). Whether these results are relevant in sepsis-mediated lung injury needs to be determined. Finally, the data from Dal-Pizzol and colleagues (7) from their cecal ligation and puncture sepsis model raise the question of whether bombesin-like peptides are released locally within the abdominal cavity by peritoneal macrophages and gut neuroendocrine cells, and then reach the airspaces via the bloodstream or mesenteric lymphatic vessels where they can stimulate immune cells within the airspaces. Alternatively, proinflammatory cytokines released within the peritoneal cavity could circulate to the lungs to stimulate pulmonary immune and neuroendocrine cells to release these neuropeptides. The ability of proinflammatory cytokines released within the peritoneal cavity to reach the lung and to stimulate lung epithelial cells has already been reported in a model of lung injury induced by intestinal ischemia and reperfusion (15). Of note, there was no increase in the plasma levels of GRP in a model of cecal ligation and puncture in rats (16). The results of these studies therefore favor the second hypothesis, although additional studies will be needed to definitively answer this important question.

Dal-Pizzol and colleagues have provided new insights regarding the mechanisms that control pulmonary inflammation in sepsis-induced lung injury. Bombesin-like peptides act as positive modulators of the lung inflammation elicited by locally or systemically released bacterial products. Because the inhibition of the GRP receptor is also protective 6 hours after establishment of the peritonitis in the cecal ligation and puncture model, inhibition of cell signaling induced by bombesin-like peptides should be explored as a new therapeutic option in the treatment of sepsis-induced lung injury. Finally, whether pulmonary neuroendocrine cells are involved in mediating the release of bombesin-like peptides after onset of a septic insult to the lung warrants further studies.

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