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Indinavir Plus Methylprednisolone Ameliorates Experimental Acute Lung Injury In Vitro and In Vivo

Indinavir Plus Methylprednisolone Ameliorates Experimental Acute Lung Injury In Vitro and In Vivo

Yunxia Ji, Guanghua Zhang, Haibo Zhu, Defang Li, Wanglin Jiang

Shock. 2018 Feb;49(2):196-204.

PMID: 28562480

Abstract:

Background:
An abnormal HMGB1 activation plays a key role in the pathogenesis of ALI.
Methods:
In this study, the effects of Indinavir plus methylprednisolone on the LPS-mediated activation in human pulmonary microvascular endothelial cells (HPMECs), on the injury of AT I in vitro, and on rats with LPS-induced two-hit model with or without methylprednisolone were investigated.
Results:
Indinavir treatment resulted in a reduction of HMGB1, its receptor TLR-4, and HMGB1's downstream p-NF-κB, attenuating a decrease of VE-cadherin in LPS-stimulated HPMECs. Apoptosis of AT I was attenuated with an increase of RAGE and aquaporin 5. Compared to methylprednisolone alone, methylprednisolone plus Indinavir attenuated the decrease of GRα and IκB-α in cytoplasm and avoid GRα deficiency in LPS-stimulated HPMECs for 96 h, attenuated the increase of p-NF-κB in nucleus. Indinavir ameliorated histopathological changes of two-hit ALI model of rats with reductions in microvascular permeability, lower HMGB1, TLR4, p-NF-κB, and MPO expression, whereas higher RAGE, aquaporin 5, and VE-cadherin in LPS-instilled lungs. Compared to methylprednisolone alone, methylprednisolone plus Indinavir attenuated the decrease of GRα and IκB-α in cytoplasm, decreased p-NF-κB in nucleus of lung tissue of two-hit ALI rats, and enhanced the anti-inflammatory effect of methylprednisolone for avoiding GRα deficiency.
Conclusion:
It demonstrated that Indinavir prevented experimental ALI model of rats by modulating the HMGB1/TLR-4 pathway to resolve systemic inflammation response in a greater degree with methylprednisolone, reduced the use time and dose of methylprednisolone, and avoided GRα deficiency in ALI and ARDS.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP180683378	Indinavir		180683-37-8	Price

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