Role of substance P in hydrogen sulfide-induced pulmonary inflammation in mice

Abstract

We have shown earlier that H(2)S acts as a mediator of inflammation. In this study, we have investigated the involvement of substance P and neurogenic inflammation in H(2)S-induced lung inflammation. Intraperitoneal administration of NaHS (1-10 mg/kg), an H(2)S donor, to mice caused a significant increase in circulating levels of substance P in a dose-dependent manner. H(2)S alone could also cause lung inflammation, as evidenced by a significant increase in lung myeloperoxidase activity and histological evidence of lung injury. The maximum effect of H(2)S on substance P levels and on lung inflammation was observed 1 h after NaHS administration. At this time, a significant increase in lung levels of TNF-alpha and IL-1beta was also observed. In substance P-deficient mice, the preprotachykinin-A knockout mice, H(2)S did not cause any lung inflammation. Furthermore, pretreatment of mice with CP-96345 (2.5 mg/kg ip), an antagonist of the neurokinin-1 (NK(1)) receptor, protected mice against lung inflammation caused by H(2)S. However, treatment with antagonists of NK(2), NK(3), and CGRP receptors did not have any effect on H(2)S-induced lung inflammation. Depleting neuropeptide from sensory neurons by capsaicin (50 mg/kg sc) significantly reduced the lung inflammation caused by H(2)S. In addition, pretreatment of mice with capsazepine (15 mg/kg sc), an antagonist of the transient receptor potential vanilloid-1, protected mice against H(2)S-induced lung inflammation. These results demonstrate a key role of substance P and neurogenic inflammation in H(2)S-induced lung injury in mice.

Hydrogen Sulfide Up-Regulates Substance P in Polymicrobial Sepsis-Associated Lung Injury

“…Activation of TRPV1 thereby results in an influx of Ca 2ϩ and induces depolarization of nerves and SP release from nerve terminals (36). Similarly, our previous study has also shown that ablation of sensory nerves with capsaicin or pretreatment with capsazepine, a TRPV1 antagonist, protected mice from H 2 S-induced lung inflammation (25). In light of the data obtained from the present study and earlier studies, we propose that under different conditions, H 2 S may regulate the release or production of SP by different pathways, including up-regulating the PPT-A gene and stimulating TRPV1.…”

“…We have previously reported that i.p. administration of NaHS in normal mice caused a significant rise in the circulatory level of SP in a dose-dependent manner, coupled with obvious lung inflammation (25). Similarly, in rat bladder, H 2 S at a physiological concentration was capable of stimulating capsaicin-sensitive primary afferent neurons with a consequent release of tachykinin, in turn leading to the contractile response of the smooth muscles (22,23).…”

“…In contrast, our previous study has demonstrated that i.p. injection of NaHS, an H 2 S donor, evoked the release of SP in a dose-and time-dependent manner and that SP, in turn, contributed to lung inflammation by acting through NK1R (25). This provides some evidence for the role of SP in H 2 S-induced lung inflammation.…”

“…In light of the data obtained from the present study and earlier studies, we propose that under different conditions, H 2 S may regulate the release or production of SP by different pathways, including up-regulating the PPT-A gene and stimulating TRPV1. For example, when the airways and urinary bladder are stimulated with NaHS for a short time, H 2 S may induce the activation of TRPV-1 (22)(23)(24)(25). If H 2 S persistently exists in an already inflamed site, such as sepsis-induced lung injury, the gas may participate in provoking PPT-A gene expression.…”

Hydrogen sulfide and inflammation: the good, the bad, the ugly and the promising

“…Similarly, pretreatment of rats with PAG for 1 h prior to blood withdrawal was also protective as PAG increased heart rate recovery time, significantly reduced liver, lung and plasma levels of TNF-a and IL-6 and, in the liver, PAG reduced neutrophilic accumulation and tissue damage [35]. Conversely, administration of H 2 S donors based on sulfide salts (see later), such as sodium hydrosulfide (NaSH) to animals either alone or in combination with LPS, induce marked hypotension, liver, lung and kidney inflammation and aggravated multiple organ injury through upregulation of tissue NF-kB, p38 and ERK1/2 signaling [36][37][38].…”