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
- 14Citations
- 19Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations14
- Citation Indexes14
- 14
- CrossRef13
- Captures19
- Readers19
- 19
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
http://www.sciencedirect.com/science/article/pii/S0022356524191331; http://dx.doi.org/10.1124/jpet.115.224832; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84941687080&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/26243739; https://linkinghub.elsevier.com/retrieve/pii/S0022356524191331; https://dx.doi.org/10.1124/jpet.115.224832; https://jpet.aspetjournals.org/content/355/1/86
Elsevier BV
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