A combination of thalidomide and clarithromycin prevents acute lung inflammation in mice suffering from Klebsiella pneumoniae B5055 induced pneumonia

Abstract

Background Despite existing antibiotic therapies, acute lung injures due to acute lung infections (i.e. pneumonia) are a major cause of mortality and morbidity in both developing as well as developed countries. Agents with potent antiinflammatory as well as immunomodulatory properties are required to prevent tissue injury. These agents should be able to suppress the deleterious effects of inflammation, while leaving the protective response intact. In the present study a combination of thalidomide (THD) and clarithromycin (CLM) is used to observe their tissue protective effect in mouse model of acute lung infection induced by Klebsiella pneumoniae B5055. The two are used together as clarithromycin has both antibacterial as well as antiinflammatory properties and thalidomide has immunomodulatory property. Methods Pneumonia was induced by intranasal instillation of Klebsiella pneumoniae B5055 (104 cfu/ml) by holding the mice in upright position without any anaesthesia. Experimental animals were divided into four groups (i.e. Group A; control (oral saline), Group B; clarithromycin (CLM) (30 mg/kg/day/os), Group C; Thalidomide (THD) ((30 mg/kg/po/day), and Group D; a combination of both thalidomide and clarithromycin (CLM+ THD). At designated period of time (1, 2, 3, 5 and 7 days) mice were euthanized by cervical dislocation and lungs were harvested and homogenized in 1 ml of sterile normal saline under sterile conditions. The lung homogenate was used for measuring bacterial load, malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) and pro-inflammatory (i.e. IL-1α, IL-6, TNF-α) anti-inflammatory (i.e. IL-10) cytokine levels in lungs. Histopathological examination of the lungs was also carried out for marking inflammatory lung damage and neutrophil infiltration. Results Clarithromycin (CLM) and thalidomide (THD) also exerted the protective immunomodulatory action when given alone. However, the combination (CLM + THD) not only significantly (p < 0.05) decreased the bacterial load in lungs of mice infected with Klebsiella pneumoniae B5055 but also significantly (p < 0.05) decreased neutrophil infiltration into the lungs. The combination also significantly (p < 0.05) decreased myeloperoxidase (MPO), malondialdehyde (MDA) and nitric oxide (NO) generation along with a significant (p < 0.05) reduction in the levels of pro-inflammatory cytokines (i.e. TNF-α, IL-6 and IL-1α). This combination acted in a synergistic way and resulted in reduced tissue injury as observed in histopathological sections of lung tissue. Conclusions Thus, thalidomide and clarithromycin together synergistically prevented acute lung inflammation occurring during acute lung infection. This combination has a great potential as an immunomodulatory approach during acute infections causing acute inflammation.L6190442292017-11-07 <br />