Low-dose Pethidine Inhibits Cigarette Smoking-induced Acute Pulmonary Inflammation In Guinea Pigs

INTRODUCTIONWe know that cigarette smoking can induce chronic lung injury and cause severe lung disorders. The intrinsic components in the cigarettes and some chemical compounds produced when burned could evoke oxidative reactions and inflammatory processes in lung, leading to structure destruction and function disorder.However, the acute effect of cigarette smoking on airways has attracted less attention. The pathophysiologic processes of acute smoking on airways and the underlying mechanism have not been completely elucidated. Thus, investigation of acute responses to cigarette smoke and the underlying mechanism is helpful to study the smoke-induced acute lung injury and drug preventions.In a previous study, we have demonstrated the initial neurogenic reaction induced by ten tidal breaths of cigarette smoke inhalation, evidenced by immediate increase of pulmonary resistance (R_l) and decrease of dynamic lung compliance (Cdyn) in guinea pigs. These initial reactions peaked quickly in 1 min and then gradually declined toward the baseline in 10 min. It has been proved that cigarette smoke exposure stimulates the afferent sensory nerve in airways to trigger the release of tachykinins directly from the fiber endings and further to increase the release of acetycholine (Ach) from the cholinergic nerves, leading to evoke the initialneurogenic response. The injurious reactions mainly localized in large airways in the initial phase; And the manifestations of the pulmonary parenchymal injury was just about to be evident. Then, we consider that what the pulmonary injurious responses will development as the smoke amount increases and time progresses? And whether the initial neurogenic response plays an important role in producing the delayed lung injury?In order to better understand whether the initial neurogenic reaction plays an important role in producing the acute delayed lung injury caused by smoke inhalation, we observed the pulmonary reactions several hours after smoke exposure or even in a longer period of time. Besides the reactions of microvascular permeability and pulmonary mechanical function, we further investigated some reactions occurred in relative late phase, such as the cell counts and differential cell profile in BALF, the level of NO and the activities of NOS.Animal experiments have primarily proved that opioid-receptor agonists, in very low dosage, could inhibit initial neurogenic reactions in airways caused by sensory irritation. Consistent with these reports, in a previous study, we also demonstrated that low-dose pethidine significantly reduced bronchoconstriction and plasma exudation, the initial airway responses after smoke exposure (data not shown).Thus, based on these observations, the aim of this study is: (1) to clarify the delayed responses after exposure to 360 ml of cigarette smoke during 2 hours; (2) further to determine whether low-dose pethidine could inhibit the cigarette smoking-induced delayed pulmonary injury and the intensity of this inhibition, the underlying mechanism is also investigated.OBJECTIVE1 The microvascular permeability both in trachea and pulmonary parenchyma tissue was determined after exposure to 360 ml of cigarette smoke during 2 h;2 The airway resistance and dynamic lung compliance were studied after exposure to 360 ml of cigarette smoke during 2 h;3 We studied the cellular profile in BALF after exposure to 360 ml of cigarette smoke during 2 h;4 We also investigated NO content and NOS activities after exposure to 360 ml of cigarette smoke during 2 h;5 Finally, we determined whether low-dose pethidine could inhibit the smoking-induced delayed pulmonary injury and the underlying mechanism.MATERIALS1 AnimalsHartley guinea pigs of either sex weighing 350~450g were purchased from Laboratory Animal Center of Medical School of Zhejiang University (Grade II, Certificate No: 20030015).2 Drugs and ReagentsPethidine (meperidine, Shenyang First Pharmaceutical Factory); naloxone hydrochloride (Beijing Four-ring Pharmaceutical Co. Ltd.); nitric oxide (Nanjing Jiancheng Bioengineering...