capsazepine and Pneumonia

The cannabinoid system is known to be involved in the regulation of inflammatory processes. Therefore, drugs targeting cannabinoid receptors are considered as candidates for anti-inflammatory and tissue protective therapy. We demonstrated that the prototypical cannabinoid agonist R(+)WIN55,212-2 (WIN) reduced the secretion of matrix metalloproteinase-9 (MMP-9) in a murine model of cigarette-smoke induced lung inflammation. In experiments using primary cells and cell lines of the monocyte-macrophage-system we found that binding of the cannabinoid-receptor agonist WIN to a stereo-selective, specific binding site in cells of the monocyte-macrophage-system induced a significant down-regulation of MMP-9 secretion and disturbance of intracellular processing, which subsequently down-regulated MMP-9 mRNA expression via a ERK1/2-phosphorylation-dependent pathway. Surprisingly, the anti-inflammatory effect was independent from classical cannabinoid receptors. Our experiments supposed an involvement of TRPV1, but other yet unidentified sites are also possible. We conclude that cannabinoid-induced control of MMP-9 in the monocyte-macrophage system via a cannabinoid-receptor independent pathway represents a general option for tissue protection during inflammation, such as during lung inflammation and other diseases associated with inflammatory tissue damage.

Topics: Animals; Benzoxazines; Binding Sites; Bone Resorption; Bronchoalveolar Lavage Fluid; Capsaicin; Cell Differentiation; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Gene Expression Regulation, Enzymologic; Glycosylation; Humans; Macrophages; Matrix Metalloproteinase 9; Mice; Microglia; Monocytes; Morpholines; Naphthalenes; Osteoclasts; Phosphorylation; Pneumonia; PPAR gamma; Receptors, Cannabinoid; rho GTP-Binding Proteins; Signal Transduction; TRPV Cation Channels

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.

Topics: Air Pollutants; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biphenyl Compounds; Capsaicin; Female; Hydrogen Sulfide; Inflammation Mediators; Lung; Male; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Neurokinin-1 Receptor Antagonists; Peroxidase; Pneumonia; Protein Precursors; Substance P; Tachykinins; TRPV Cation Channels