Effects of different doses of methylprednisolone therapy on acute respiratory distress syndrome: results from animal and clinical studies

Abstract

Background: The optimal dose of glucocorticoids for acute respiratory distress syndrome (ARDS) is uncertain. This study aimed to evaluate the effects of different doses of methylprednisolone on sepsis-induced acute lung injury (ALI) rats and a cohort of moderate and severe ARDS patients.

Methods: ALI rats, challenged with lipopolysaccharide, were randomly received intraperitoneal injection of normal saline (model group) and different doses of methylprednisolone (0.5, 2, 8 mg/kg, named as low-, moderate- and high-dose group, respectively) for 5 days. The body weight changes of rats, inflammatory factors in bronchoalveolar lavage fluid (BALF), lung wet/dry ratio, histopathological score, and the mRNA expressions of glucocorticoid receptor α (GRα), GRβ and nuclear factor-κB (NF-κB) were measured. Forty moderate and severe ARDS patients were treated with standard of care or plus different doses of methylprednisolone (40, 80, 120 mg/day, named as low-, moderate- and high-dose group, respectively) for 5 days. Clinical outcomes were PaO₂/FiO₂ ratio and C-reactive protein (CRP) level at day 5, intubation rate, hospital stay, 28-day mortality, and adverse events rate.

Results: In animal experiment, different doses of methylprednisolone could increase the body weight of rats, and reduce inflammatory factors in BALF and the degree of lung injury compared with model group. The efficacy of methylprednisolone at moderate-dose was better than that at low-dose, but was equivalent to that at high-dose, which was consistent with the differential changes in the mRNA expression of GRα, GRβ and NF-κB. In clinical study, the moderate-dose group was associated with higher PaO₂/FiO₂ ratio and lower CRP level. No significant difference in other clinical outcomes among groups was detected.

Conclusions: This study showed that the efficacy of methylprednisolone in ARDS treatment was not always dose-dependent due to the differential regulation of related receptors. The moderate-dose of methylprednisolone may be the potential optimal dose for ARDS treatment, which needs to be further verified by larger clinical trials.

Keywords: Acute lung injury; Acute respiratory distress syndrome; Animal model; Dose; Glucocorticoids; Methylprednisolone.

Fig. 1

Effects of different doses of methylprednisolone on the body weight of rats. “Day 0”represents the time before treatment, and “Day 5” represents the fifth day of treatment. The height of the bar chart represents the value of the mean, and the black dot at the top of the bar chart represents the individual data from each animal. T-test was used to compare the body weight of rats before and after treatment, and the data between the blank control group and the model group. The comparison between the model group and three different concentrations of methylprednisolone treatment groups was performed by One-way analysis of variance. *P < 0.05 versus model group

Fig. 2

Effects of different doses of methylprednisolone on the lung wet/dry ratio in rats. The height of the bar chart represents the value of the mean, and the black dot at the top of the bar chart represents the individual data from each animal. T-test was used to compare the data between the blank control group and the model group. The comparison between the model group and three different concentrations of methylprednisolone treatment groups was performed by One-way analysis of variance. *P < 0.01 versus model group; **P < 0.01 versus low-dose group

Fig. 3

Effects of different doses of methylprednisolone on the WBC and neutrophil counts in BALF of rats. A WBC count; B neutrophil count. The height of the bar chart represents the value of the mean, and the black dot at the top of the bar chart represents the individual data from each animal. T-test was used to compare the data between the blank control group and the model group. The comparison between the model group and three different concentrations of methylprednisolone treatment groups was performed by One-way analysis of variance. *P < 0.01 versus model group; **P < 0.05 versus low-dose group

Fig. 4

Effects of different doses of methylprednisolone on the concentrations of IL-6 and TNF-α in BALF of rats. A IL-6 concentration; B TNF-α concentration. The height of the bar chart represents the value of the mean, and the black dot at the top of the bar chart represents the individual data from each animal. T-test was used to compare the data between the blank control group and the model group. The comparison between the model group and three different concentrations of methylprednisolone treatment groups was performed by One-way analysis of variance. *P < 0.01 versus model group; **P < 0.05 versus low-dose group

Fig. 5

Effects of different doses of methylprednisolone on histopathological change of lung tissue in rats. Hematoxylin-and-eosin-stained sections of lung tissue were observed under a light microscope (original magnification × 100). Representative image of each group was revealed. A blank control group; B model group, yellow arrow indicates the alveolar hemorrhage, red arrow indicates the infiltration or aggregation of neutrophils in the airspace, and green arrow indicates the thickening of alveolar wall; C low-dose group; D moderate-dose group; E high-dose group. F histopathological scores of lung tissues in each group. The height of the bar chart represents the value of the mean, and the black dot at the top of the bar chart represents the individual data from each animal. T-test was used to compare the data between the blank control group and the model group. The comparison between the model group and three different concentrations of methylprednisolone treatment groups was performed by One-way analysis of variance. *P < 0.01 versus model group; **P < 0.01 versus low-dose group

Fig. 6

Effects of different doses of methylprednisolone on mRNA expression of GRα, GRβ and NF-κB in lung tissue of rats. A GRα mRNA expression; B GRβ mRNA expression; C NF-κB mRNA expression. The height of the bar chart represents the value of the mean, and the black dot at the top of the bar chart represents the individual data from each animal. T-test was used to compare the data between the blank control group and the model group. The comparison between the model group and three different concentrations of methylprednisolone treatment groups was performed by One-way analysis of variance. *P < 0.05 versus model group; **P < 0.05 versus low-dose group