(i) Activation of nAChR by nicotine, choline, and PNU-282987 (a specific nAChR agonist) decreased excess lung water and lung vascular permeability and reduced protein concentration in the BAL. (ii) Deficiency of nAChR resulted in a 2-fold increase in excess lung water and lung vascular permeability.
(i) Nicotine treatment reduced the LPS-mediated infiltration of leukocytes and edema as evidenced by decreased BALF inflammatory cells, myeloperoxidase, and protein. (ii) Nicotine also downregulated lung production of proinflammatory chemokines and cytokines. (iii) Intranasal inoculation with GTS-21 also dose dependently inhibited TNF-alpha release into the lung compartment after intrapulmonary delivery of LPS in mice in vivo.
(i) Administration of nAChR agonists reduced bronchoalveolar lavage MIP-2 production and transalveolar neutrophil migration and reduced mortality in E. coli pneumonia. (ii) Vagal denervation increased MIP-2 production and airway neutrophil accumulation and increased mortality. (iii) nAChR deficient mice developed severe lung injury and had higher mortality compared with wildtype mice.
(i) Exacerbation of P. aeruginosa-induced lung injury and mortality by prior stroke is reduced by loss of nAChR receptors. (ii) Genetic deletion of the nAChR attenuates the effect of stroke on bacterial clearance in P. aeruginosa pneumonia. (iii) Pretreatment with PNU-282987, a pharmacologic activator of the nAChR significantly increased lung injury caused by P. aeruginosa pneumonia, significantly decreased the release of KC, a major neutrophil chemokine, and significantly decreased intracellular bacterial killing by a mouse alveolar macrophage cell line and primary mouse neutrophils.
(i) Nicotine treatment was associated with a transiently enhanced growth of S. pneumoniae in both lungs and blood. (ii) Mice treated with nicotine showed enhanced lung inflammation at 24 h after infection. (iii) Both lung and plasma concentrations of the proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma were higher in nicotine-treated animals at this time point.
Ventilator-induced lung injury (VILI) (mouse and rats)
Direct: lung epithelial cells
(i) Pharmacological pretreatment with PNU-282987 strongly decreased lung injury and lung IL-6 and substance P contents and nearly abolished the increase in plasmatic IL-6 levels. (ii) Vagal stimulation was able to maintain the respiratory parameters close to those obtained in controls and reduced lung inflammation except when associated to nicotinic receptor blockader MLA. (iii) Stimulation of the cholinergic anti-inflammatory pathway with GTS-21 attenuates MV-induced release of TNF-, which was associated with reduced lung injury. (iv) Vagotomy exacerbates lung injury from VILI in mice as demonstrated by increased wet-to-dry ratio, infiltration of neutrophils, and increased IL-6.
(i) Vagotomy enhanced the LPS-induced pulmonary, but not systemic proinflammatory cytokine SP rats, but not in MV animals (TNF-α, IL-6, and KC compared to sham), and resulted in decreased pO2 (compared to sham-operated animals). (ii) VNS did not affect any of the studied parameters in both SP and MV animals. (iii) MV with moderate tidal volumes potentiates the pulmonary inflammatory response elicited by systemic LPS administration. (iv) No beneficial effects of vagus nerve stimulation performed following LPS administration were found.
VNS is protective in LPS challenge but not in LPS + MV model
(i) In the dogs with normal lungs, bilateral vagotomy per se did not cause lung injury during 3 h of observation. (ii) In oleic acid-induced ALI, vagotomy significantly deteriorated pulmonary edema by increasing pulmonary intravascular pressures. (iii) Inhibition of vagal or sympathetic innervation will aggravate pulmonary edema in the dog.
(i) The airway reactivity to acetylcholine at 2 weeks after infection was increased by 2.3 to 6.5 times the normal value in terms of the acetylcholine provocative concentration after influenza viral infection. (ii) The virus was apparently transported from the respiratory mucosa to the CNS directly and decussately via the vagus nerve and centrifugally to the vagal ganglion of the vagotomized side. (iii) Nicotine suppressed the migration of leukocytes to the inflammation/infection site and increased the influenza titer in the lung.