Editors' ChoiceRespiratory Distress

Novel Peptide to Treat Sepsis-Induced Acute Lung Injury

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Science Translational Medicine  19 Jan 2011:
Vol. 3, Issue 66, pp. 66ec7
DOI: 10.1126/scitranslmed.3002123

Sepsis is an often fatal condition that develops when bacterial infection leads to a whole-body inflammatory response. This excessive systemic inflammation may cause blood clots that block the flow of blood to the vital organs, resulting in organ dysfunction and eventual death. The lungs are the most susceptible tissue to sepsis-induced organ failure, and more than 50% of patients with sepsis develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Treatment of ARDS is mostly symptomatic because the mechanisms underlying the pathological changes are not well understood.

Protein kinase C-δ (δ-PKC) regulates proinflammatory signaling in a variety of cells, including neutrophils, epithelial cells, and endothelial cells. In a rodent model of ARDS caused by intra-abdominal sepsis, δ-PKC phosphorylation was increased in the lung. Now, Kilpatrick et al. demonstrate that selective inhibition of δ-PKC using a δ-PKC TAT inhibitory peptide, which can cross the plasma membrane into cells, attenuates inflammation and acute lung injury in this model of ARDS.

The authors induced experimental ARDS in rats and then treated both ARDS-affected and control rats with either δ-PKC TAT inhibitory peptide or the diluent (phosphate-buffered saline). Treatment with a single dose of δ-PKC TAT inhibitory peptide dramatically reduced pulmonary and circulating chemokines, mitigated inflammatory cell influx, reduced capillary leak, and limited the development of pulmonary edema in the ARDS rat model. These effects were largely attributed to the inhibition of δ-PKC phosphorylation, which may inhibit chemokine synthesis and limit leukocyte infiltration.

Peptide drugs are the most recent trend in drug discovery, and significant improvements are being made to overcome their shortcomings, which include high manufacturing costs, short half-life, and limited in vivo bioavailability. The δ-PKC TAT inhibitory peptide is clinically amenable and is currently being studied in a clinical trial for the treatment of acute myocardial infarction. Thus, the δ-PKC TAT inhibitory peptide may emerge as a promising drug for the treatment of ARDS.

L. E. Kilpatrick et al., Protection against sepsis-induced lung injury by selective inhibition of protein kinase C-δ (δ-PKC). J. Leukoc. Biol. 89, 3–10 (2011). [Abstract]

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