Lobe-specific modulation of B16MET melanoma lung metastases by nephrilin peptide

Abstract

Aim: Nephrilin peptide modulates systemic immune responses to trauma in contexts characterized by simultaneous inflammation and immunosuppression. This study explores the possibility that nephrilin peptide may modulate lung metastasis, which also occurs in an environment of concurrent inflammation and immunosuppression.

Methods: B16MET melanoma cells were injected via the tail vein of mice and the development of lung metastases was recorded in animals treated with nephrilin peptide or vehicle by subcutaneous bolus injection daily for three weeks. In a separate experiment, nephrilin was administered by subcutaneous bolus injection for seven days to study the biodistribution of peptide and possible changes to plasma cytokine levels.

Results: Nephrilin significantly suppressed B16MET lung metastases. Suppression was more effective in deep lobes with the poorest access to circulation: accessory > inferior > middle > superior. In a separate biodistribution study in mice, nephrilin showed similar biodistribution levels in kidney, liver, brain, and left lung, but significantly higher accumulation in the lobes of the right lung in a gradient that matched its effectiveness in suppressing metastases (accessory > inferior > middle). The latter environments were also characterized by significantly higher local concentrations of succinate, a proxy for lower levels of oxygenation.

Conclusion: Nephrilin accumulates preferentially in the deep lobes of the right lung in mice and inhibits B16MET right lung metastases in a lobe-specific manner.

Keywords

Nephrilin / melanoma / metastases / deep lung / lobes / anoxia / oxidative stress / immune modulation

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