CYCLOOXYGENASE MECHANISMS IN THE REGULATION OF RESPIRATORY EFFECTS OF TUMOR NECROSIS FACTOR

Abstract

Introduction. It is known that the systemic level of the major pro-inflammatory cytokine increases in many respiratory diseases such as asthma, COPD and sleep apnea [1, 2]. The lung ventilation changes and the pathological types of breathing are typical in these diseases. By the reason, the research of the respiratory effects of cytokine is actual. The aim of this study was to compare the respiratory effects of tumor necrosis factor - α (TNF-α) before and after pretreatment with diclofenac, a nonspecific cyclooxygenase (COX) inhibitor. Materials and methods. Тhe experiments were performed in tracheostomized anaesthetized with urethane rats. A respiratory flow head connected to a pneumotachometer (AD Instruments ML141 Spirometer, Dunedin, New Zealand) was used to measure peak airflow and respiratory rate. The hypoxic ventilatory response was measured by using rebreathing with hypoxic gas mixture before and after the tail vein injection of TNF-α (10 μg/rat). In order to determine the role of the cyclooxygenase pathway in the ventilatory effects of TNF-α, introperitoneal administration of diclofenac, a nonspecific COX inhibitor, was used (0.5 mg/rat). Results and discussion. We have shown that the increase in level of TNF-α in blood increased the parameters of respiration such as minute ventilation (by 40%), tidal volume (by 18%), and the mean inspiratory flow (by 33%). The slope of the hypoxic ventilatory response decreased from 6.06 ± 0.91 to 3.48 ± 0.38 ml/min-1 mmHg-1 (by 40%) 40 min after administration of TNF-α (p < 0.05), the slope of tidal volume and mean inspiratory flow also decreased (by 27%) (p < 0.05). After pretreatment with diclofenac, the influence of TNF-α on breathing was dampened, as no significant changes were observed. Conclusion. We concluded that the elevation of inflammatory cytokine level in blood intensifies ventilation during the resting breathing that may be associated with increased central inspiratory activity. At the same time TNF-α reduces the chemoreflex sensitivity to hypoxia, thereby worsening the compensatory capabilities of the respiratory system. Thus, the results of our study suggest participation of inflammatory cytokines in mechanisms of central breathing control and chemoreception. Diclofenac pretreatment eliminated the respiratory effects of TNF-α. The data indicate that the ability of TNF-α to enhance basal ventilation and to reduce the ventilatory hypoxic response is mediated by the COX pathway.