Monoamino-oxidase-A function and potential benefit of its inhibition in sepsis

Introduction

The use of hydrocortisone (HC) for treatment of septic shock is controversially discussed. Microarray data from the CORTICUS trial showed the transcript encoding monoamino-oxidase-A (MAOA) as one of the strongest upregulated genes. Due to its involvement in generating reactive oxygen species (ROS) and apoptosis, MAOA might play an important role in infection and development of organ dysfunction in these patients. Blocking MAOA with the specific inhibitor clorgylin (CL) may provide a new therapeutic intervention for sepsis. The present study investigates the function of MAOA in sepsis and the potential benefits of its inhibition.

Methods

A total of 15 patients with severe sepsis or septic shock were enrolled and compared with 10 healthy controls. As a polymicrobial sepsis model, 16-week-old C57BL6 mice were injected intraperitoneally with 5 μg/g BW characterized human feces. Animals were treated once a day with 35 ml/kg BW saline and 4 mg/kg BW HC + 0.25 mg/kg BW CL. MAOA mRNA was quantified by quantitative PCR, and protein levels were measured by flow cytometry. Phagotests determining phagocytotic activity were performed following the manufacturer's instructions. For ex vivo stimulation, whole blood of healthy individuals was incubated with HC (50 μg/ml) and LPS (100 ng/ml). For laboratory and microbiological analyses, routine laboratory procedures were used. ROS were measured by difluorodihydrofluorescein diacetate and flow cytometry.

Results

Quantitative PCR showed a significant increase of MAOA mRNA expression in patients with sepsis versus healthy controls (eightfold, P < 0.05). The same is true for protein levels of MAOA (1.5-fold, P < 0.05). Blocking of MAOA by CL enhanced phagocytosis ex vivo (140%, P < 0.05). In the animal model after MAOA inhibition, the survival rate was significantly higher (risk reduction 40%, P < 0.05) and less bacterial burden was found in the blood, lung, and liver (1 log, P < 0.05). Furthermore, less organ damage shown by LDH, ASAT and ALAT was observed (P < 0.05). These results were associated with less ROS production in granulocytes (P < 0.05).

Conclusions

MAOA is strongly upregulated during severe sepsis on RNA as well as on protein level. In septic mice, higher survival rates were observed by blocking MAOA. Inhibition of MAOA might have potential in sepsis and so provide a novel method for therapeutic intervention.