Substance P and neutral endopeptidase in development of acute respiratory distress syndrome following fire smoke inhalation

Abstract

To characterize the tachykininergic effects in fire smoke (FS)-induced acute respiratory distress syndrome (ARDS), we designed a series of studies in rats. Initially, 20 min of FS inhalation induced a significant increase of substance P (SP) in bronchoalveolar lavage fluid (BALF) at 1 h and persisted for 24 h after insult. Conversely, FS disrupted 51.4, 55.6, 46.3, and 43.0% enzymatic activity of neutral endopeptidase (NEP, a primary hydrolyzing enzyme for SP) 1, 6, 12, and 24 h after insult, respectively. Immunolabeling density of NEP in the airway epithelium largely disappeared 1 h after insult due to acute cell damage and shedding. These changes were also accompanied by extensive influx of albumin and granulocytes/lymphocytes in BALF. Furthermore, levels of BALF SP and tissue NEP activity dose dependently increased and decreased, respectively, following 0, low (10 min), and high (20 min) levels of FS inhalation. However, neither the time-course nor the dose-response study observed a significant change in the highest affinity neurokinin-1 receptor (NK-1R) for SP. Finally, treatment (10 mg/kg im) with SR-140333B, an NK-1R antagonist, significantly prevented 20-min FS-induced hypoxemia and pulmonary edema 24 h after insult. Further examination indicated that SR-140333B (1.0 or 10.0 mg/kg im) fully abolished early (1 h) plasma extravasation following FS. Collectively, these findings suggest that a combination of sustained SP and NEP inactivity induces an exaggerated neurogenic inflammation mediated by NK-1R, which may lead to an uncontrolled influx of protein-rich edema fluid and cells into the alveoli as a consequence of increased vascular permeability.

Substance P acts via the neurokinin receptor 1 to elicit bronchoconstriction, oxidative stress, and upregulated ICAM-1 expression after oil smoke exposure

“…This was manifested by thickening of the alveolar capillary membrane, interstitial pneumonitis, peribronchiolar inflammation, and sloughing and necrosis of the bronchiolar epithelium. These observations are consistent with previously published findings (1,22).…”

“…Several studies have demonstrated that SP is a proinflammatory agent that influences various signaling transduction pathways within a complex inflammatory network by C-fiber afferent stimulation following external stimulation (1,4,9,14,22). In vivo studies have demonstrated the efficacy of antioxidants and free radical scavengers in ameliorating increases in endogenous SP levels (which may result in increased microvascular permeability via upregulated ICAM-1 expression, edema, and severe hypoxia) (11).…”

Hypoxia upregulates lung microvascular neurokinin-1 receptor expression

“…This ligand-receptor pair mediates neurogenic inflammation in the airways via cytokines including IL-1, IL-6, and TNF-␣ (14,20). In addition, substance P levels are markedly elevated in pulmonary edema fluid from ARDS patients (6), and the NK-1 receptor has been implicated in the pathophysiology of lung injury associated with pancreatitis (13), smoke inhalation (30), and viral infections (23) including respiratory syncytial virus (11).…”

Substance P antagonist CP-96345 blocks lung vascular leakage and inflammation more effectively than its stereoisomer CP-96344 in a mouse model of smoke inhalation and burn injury

“…The NK1 receptors involved in plasma leakage are located on the endothelial cells of post capillary venules and collecting venules. Within seconds of the activation of NK1 receptors by substance P, gaps form in the endothelium of target vessels (Wong et al 2003 and 2004). The endothelial gaps are transient, and the leak normally ends in a few minutes (McDonald et al 1996).…”