Sepsis-induced lung injury remains a leading cause of death in ICUs. Protein Kinase C-delta (PKCδ) has been identified as a critical regulator of the acute inflammatory response. In the present study, whole-body organ biodistribution and pulmonary cellular distribution of a TAT-conjugated PKCδ inhibitory peptide (PKCδ-TAT) was determined following intratracheal (IT) delivery in control and septic rats to ascertain the impact of disease pathology on biodistribution and efficacy. There was negligible lung uptake of radiolabeled peptide upon intravenous delivery, while IT administration resulted in lung retention of >65% with minimal uptake in liver or kidney. IT delivery of a fluorescent-tagged peptide demonstrated uniform spatial distribution and cellular uptake throughout the peripheral lung. IT delivery of PKCδ-TAT in a rat sepsis model reduced PKCδ activation and acute lung inflammation, resulting in improved lung function and gas exchange. These studies establish a functional connection between peptide spatial distribution and efficacy.
See article at J Pharmacol Exp Ther 2015, 355:86-98.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics