Thoracic vagal efferent nerve stimulation evokes substance P-induced early airway bronchonstriction and late proinflammatory and oxidative injury in the rat respiratory tract

Electrical stimulation of efferent thoracic vagus nerve (TVN) evoked neurogenic inflammation in respiratory tract of atropine-treated rats by an undefined mechanism. We explored whether efferent TVN stimulation via substance P facilitates neurogenic inflammation via action of nuclear factor-κB (NF-κB) activation and reactive oxygen species (ROS) production. Our results showed that increased frequency of TVN stimulation concomitantly increased substance P-enhanced hypotension, and bronchoconstriction (increases in smooth muscle electromyographic activity and total pulmonary resistance). The enhanced SP release evoked the appearance of endothelial gap in silver-stained leaky venules, India-ink labeled extravasation, and accumulations of inflammatory cells in the respiratory tract, contributing to trachea plasma extravasation as well as increases in blood O ₂^- and H₂O₂ ROS amount. L-732138 (NK₁ receptor antagonist), SR-48968 (NK₂ receptor antagonist), dimethylthiourea (H₂O₂ scavenger) or catechins (O ₂^- and H₂O₂ scavenger) pretreatment reduced efferent TVN stimulation-enhanced hypotension, bronchoconstriction, and plasma extravasation. Increased frequency of TVN stimulation significantly upregulated the expression of nuclear factor-κB (NF-κB) in nuclear protein and intercellular adhesion molecule-1 (ICAM-1) in total protein of the lower respiratory tract tissue. The upregulation of NF-κB and ICAM-1 was attenuated by NK receptor antagonist and antioxidants. In conclusion, TVN efferent stimulation increases substance P release to trigger NF-κB mediated ICAM-1 expression and O ₂^- and H₂O₂ ROS production in the respiratory tract.