Immunomodulatory Effect of Colistin and its Protective Role in Rats with Methicillin-Resistant Staphylococcus aureus-induced Pneumonia

Abstract

Objectives: Colistin is the last resort of antimicrobials against multi-drug resistant Gram-negative pathogens. Previous studies in Caenorhabditis elegans and macrophages of rats have suggested that colistin possesses the immunomodulatory properties by acting p38/MAPK pathway. Here, we aimed to confirm the immunomodulatory role of colistin in animal models.Methods: Rat model of Methicillin-resistant Staphylococcus aureus (MRSA)-induced pneumonia was established. Plasma concentrations of proinflammatory cytokines, quantitative bacteriology, histology and immunohistochemistry of lungs were assessed to compare the immunomodulatory properties of colistin pre-administration.Results: The numbers of white blood cells and granulocytes were significantly increased in the 9 mg/kg colistin pre-administration group at 72 h after infection. Levels of TNF-α, IL-6 and IL-1β in plasma after colistin pre-administration were lower compared with the infected group without treatment. Colistin pre-treatment resulted in lower bacterial counts, a dramatic decrease of cytokines and improved histopathological injury in infected lung tissues compared with the untreated animals. However, p38/MAPK inhibitor SB203580 did not fully block the above-mentioned effects caused by colistin.Conclusion: Pre-administration of colistin could attenuate an excessive inflammatory reaction and protect the lungs from MRSA-associated damages. However, these effects could not be reversed by blocking the p38/MAPK pathway alone. Collectively, the mechanism underlying the immunoregulatory effects of colistin in mammals needs to be further explored.

Dual functional therapeutics: mitigating bacterial infection and associated inflammation

“…An in vivo study was performed for colistin in a rat model of infection, and it was observed that pre-administration of colistin led to lower levels of cytokines such as TNF-α, IL-6 and IL-1β in animal plasma, compared with the infected group without treatment. 59 Colistin pre-treatment also led to reduced bacterial burden, strong reduction in cytokine levels and improved histopathological injury in infected lung tissues compared with the untreated animals. This study also demonstrated that a p38/MAPK inhibitor does not reverse the effects of colistin, thereby contradicting earlier reports about the mechanism of immunomodulation.…”

“…This study also demonstrated that a p38/MAPK inhibitor does not reverse the effects of colistin, thereby contradicting earlier reports about the mechanism of immunomodulation. 59 Followed by these studies, a randomized, double-blind, placebo-controlled crossover trial was performed to evaluate the effect of colistin on inflammatory responses in LPS-challenged healthy volunteers in a human endotoxemia model. 60 A single dose of colistin methanesulphonate through the intravenous route led to a significant reduction of the inflammatory cytokine response (IL-6, IL-8, and TNF-α) in healthy volunteers after 24 hours (Table 2).…”

The Application of Rat Models in Staphylococcus aureus Infections

“…Niu [42] MRSA B3180 SD Endotracheal intubation 2.7 × 10 8 Colistin All the rats in the infected group developed pneumonia with a marked cellular inflammatory response compared with the negative control group. In contrast to the untreated controls, rats in the colistin and SB203580 + colistin groups showed a reduction in alveolar septal thickening and cellular inflammatory infiltration.…”

Nickel Nanoparticles: Applications and Antimicrobial Role against Methicillin-Resistant Staphylococcus aureus Infections

“…The combination of β-lactam and either arbekacin or vancomycin is recommended against MRSA. Notably, granulocyte counts are also recommended for antibiotics consumption [ 50 , 51 ]. Ceftaroline fosamil has exhibited substantial anti-MRSA effects [ 52 , 53 , 54 ].…”