Methylprednisolone Treatment in Brain Death-Induced Lung Inflammation–A Dose Comparative Study in Rats

Abstract

Background: The process of brain death (BD) leads to a pro-inflammatory state of the donor lung, which deteriorates its quality. In an attempt to preserve lung quality, methylprednisolone is widely recommended in donor lung management. However, clinical treatment doses vary and the dose-effect relation of methylprednisolone on BD-induced lung inflammation remains unknown. The aim of this study was to investigate the effect of three different doses methylprednisolone on the BD-induced inflammatory response.Methods: BD was induced in rats by inflation of a Fogarty balloon catheter in the epidural space. After 60 min of BD, saline or methylprednisolone (low dose (5 mg/kg), intermediate dose (12.5 mg/kg) or high dose (22.5 mg/kg)) was administered intravenously. The lungs were procured and processed after 4 h of BD. Inflammatory gene expressions were analyzed by RT-qPCR and influx of neutrophils and macrophages were quantified with immunohistochemical staining.Results: Methylprednisolone treatment reduced neutrophil chemotaxis as demonstrated by lower IL-8-like CINC-1 and E-selectin levels, which was most evident in rats treated with intermediate and high doses methylprednisolone. Macrophage chemotaxis was attenuated in all methylprednisolone treated rats, as corroborated by lower MCP-1 levels compared to saline treated rats. Thereby, all doses methylprednisolone reduced TNF-α, IL-6 and IL-1β tissue levels. In addition, intermediate and high doses methylprednisolone induced a protective anti-inflammatory response, as reflected by upregulated IL-10 expression when compared to saline treated brain-dead rats.Conclusion: We showed that intermediate and high doses methylprednisolone share most potential to target BD-induced lung inflammation in rats. Considering possible side effects of high doses methylprednisolone, we conclude from this study that an intermediate dose of 12.5 mg/kg methylprednisolone is the optimal treatment dose for BD-induced lung inflammation in rats, which reduces the pro-inflammatory state and additionally promotes a protective, anti-inflammatory response.

Anti-inflammatory effect of thalidomide in an experimental lung donor model of brain death

“…As mentioned previously, the process of brain death leads to a pro-inflammatory state in the donor lung, which deteriorates its quality. To preserve lung quality, studies use different forms of treatment to reduce this inflammation, like we found in studies involving the use of methylprednisolone, and carbon monoxide inhalation 29 – 31 .…”

“…Pilla et al also showed in their study that 30 mg/kg of methylprednisolone, 5 and 60 min after induction of BD, intravenously also reduced the levels of TNF-α in lung tissue. In the study by Zhou et al they demonstrated that carbon monoxide inhalation was able to reduce lung injury (anti-inflammatory action, due to the reduction of IL-6 and TNF- α and antiapoptotic agents) in rats subjected to brain death 29 – 31 .…”

Current status of glucocorticoid usage in solid organ transplantation

“…Macrophage chemotaxis was attenuated with all doses of methylprednisolone, while neutrophil chemotaxis was more evident with intermediate and high doses of methylprednisolone. Considering dose-related side effects of methylprednisolone, this study suggested the intermediate dose of methylprednisolone reduced brain death-induced inflammatory responses in donors’ lungs[ 63 ]. These findings need human studies before extrapolation to routine clinical use.…”

Current Status of Glucocorticoid Usage in Solid Organ Transplantation

“…Thus, more studies are needed to understand how deficiency in the leptin signaling may switch the GC action from protection to aggravation in liver IRI and thus affect GC action in SOT of liver and other organs in humans. [63] . These findings need human studies before extrapolation to routine clinical use.…”