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

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

J Pharmacol Exp Ther

Center for Inflammation, Clinical and Translational Lung Research (M.J.M., P.A.K., J.W., M.K., S.T.B., M.R.W., L.E.K.), Department of Physiology (M.J.M., P.A.K., J.W., S.T.B., M.R.W., L.E.K.), Sol Sherry Thrombosis Research Center (M.J.M., L.C.K., L.E.K.), Departments of Pediatrics and Medicine (M.R.W.), and Department of Radiology (L.C.K.), Temple University School of Medicine, Philadelphia, Pennsylvania

Published: October 2015

AI Article Synopsis

  • Sepsis and lung injury significantly contribute to mortality in ICUs, and inhibiting protein kinase C-δ (PKCδ) shows promise as a way to protect lung function during sepsis.
  • Researchers analyzed how a special PKCδ inhibitory peptide (PKCδ-TAT) traveled in the body and targeted the lungs after being delivered directly to the airways, finding high retention in the lungs compared to minimal uptake in other organs.
  • Administration of PKCδ-TAT at surgery reduced lung inflammation and improved function, while delaying treatment to 8 hours post-surgery led to reduced effectiveness due to worsening lung injury.

Article Abstract

Sepsis and sepsis-induced lung injury remain a leading cause of death in intensive care units. We identified protein kinase C-δ (PKCδ) as a critical regulator of the acute inflammatory response and demonstrated that PKCδ inhibition was lung-protective in a rodent sepsis model, suggesting that targeting PKCδ 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 PKCδ inhibitory peptide (PKCδ-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-PKCδ-TAT) peptide demonstrated uniform spatial distribution and cellular uptake throughout the peripheral lung. IT delivery of PKCδ-TAT at the time of CLP surgery significantly reduced PKCδ 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4576664PMC
http://dx.doi.org/10.1124/jpet.115.224832DOI Listing

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