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Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C- δ Inhibitory Peptide: Impact on Indirect Lung Injury

The Journal of Pharmacology and Experimental Therapeutics, ISSN: 0022-3565, Vol: 355, Issue: 1, Page: 86-98
2015
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Article Description

Sepsis and sepsis-induced lung injury remain a leading cause of death in intensive care units. We identified protein kinase C- δ (PKC δ ) as a critical regulator of the acute inflammatory response and demonstrated that PKC δ inhibition was lung-protective in a rodent sepsis model, suggesting that targeting PKC δ is a potential strategy for preserving pulmonary function in the setting of indirect lung injury. In this study, whole-body organ biodistribution and pulmonary cellular distribution of a transactivator of transcription (TAT)–conjugated PKC δ inhibitory peptide (PKC δ -TAT) was determined following intratracheal (IT) delivery in control and septic [cecal ligation and puncture (CLP)] rats to ascertain the impact of disease pathology on biodistribution and efficacy. There was negligible lung uptake of radiolabeled peptide upon intravenous delivery [<1% initial dose (ID)], whereas IT administration resulted in lung retention of >65% ID with minimal uptake in liver or kidney (<2% ID). IT delivery of a fluorescent-tagged (tetramethylrhodamine-PKC δ -TAT) peptide demonstrated uniform spatial distribution and cellular uptake throughout the peripheral lung. IT delivery of PKC δ -TAT at the time of CLP surgery significantly reduced PKC δ activation (tyrosine phosphorylation, nuclear translocation and cleavage) and acute lung inflammation, resulting in improved lung function and gas exchange. Importantly, peptide efficacy was similar when delivered at 4 hours post-CLP, demonstrating therapeutic relevance. Conversely, spatial lung distribution and efficacy were significantly impaired at 8 hours post-CLP, which corresponded to marked histopathological progression of lung injury. These studies establish a functional connection between peptide spatial distribution, inflammatory histopathology in the lung, and efficacy of this anti-inflammatory peptide.

Bibliographic Details

Mondrinos, Mark J; Knight, Linda C; Kennedy, Paul A; Wu, Jichuan; Kauffman, Matthew; Baker, Sandy T; Wolfson, Marla R; Kilpatrick, Laurie E

Elsevier BV

Biochemistry, Genetics and Molecular Biology; Pharmacology, Toxicology and Pharmaceutics

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