{
    "abstract": "Sepsis and sepsis-induced lung injury remain a leading cause of death in intensive care units. We identified protein kinase C-\u03b4 (PKC\u03b4) as a critical regulator of the acute inflammatory response and demonstrated that PKC\u03b4 inhibition was lung-protective in a rodent sepsis model, suggesting that targeting PKC\u03b4 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\u03b4 inhibitory peptide (PKC\u03b4-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\u03b4-TAT) peptide demonstrated uniform spatial distribution and cellular uptake throughout the peripheral lung. IT delivery of PKC\u03b4-TAT at the time of CLP surgery significantly reduced PKC\u03b4 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.",
    "authors": [
        {
            "affiliation": "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.",
            "firstname": "Mark J",
            "initials": "MJ",
            "lastname": "Mondrinos"
        },
        {
            "affiliation": "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.",
            "firstname": "Linda C",
            "initials": "LC",
            "lastname": "Knight"
        },
        {
            "affiliation": "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.",
            "firstname": "Paul A",
            "initials": "PA",
            "lastname": "Kennedy"
        },
        {
            "affiliation": "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.",
            "firstname": "Jichuan",
            "initials": "J",
            "lastname": "Wu"
        },
        {
            "affiliation": "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.",
            "firstname": "Matthew",
            "initials": "M",
            "lastname": "Kauffman"
        },
        {
            "affiliation": "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.",
            "firstname": "Sandy T",
            "initials": "ST",
            "lastname": "Baker"
        },
        {
            "affiliation": "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.",
            "firstname": "Marla R",
            "initials": "MR",
            "lastname": "Wolfson"
        },
        {
            "affiliation": "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 laurie.kilpatrick@temple.edu.",
            "firstname": "Laurie E",
            "initials": "LE",
            "lastname": "Kilpatrick"
        }
    ],
    "conclusions": null,
    "copyrights": "Copyright \u00a9 2015 by The American Society for Pharmacology and Experimental Therapeutics.",
    "doi": "10.1124/jpet.115.224832",
    "journal": "The Journal of pharmacology and experimental therapeutics",
    "keywords": [],
    "methods": null,
    "publication_date": "2015-08-06",
    "pubmed_id": "26243739\n12682440\n24391146\n19698711\n18250271\n15147964\n14743496\n24532668\n16376528\n11553773\n20498779\n22983354\n15232611\n17919087\n19217767\n16146340\n24745331\n17562707\n10788556\n10227674\n19483709\n8976194\n18059334\n23899564\n20724665\n19801500\n16298009\n17921036\n16542646\n10945993\n11175248\n20936936\n23572089\n24211111\n17711319\n22823261\n18780309\n15774464\n15258728\n21633170\n12759450\n21348592\n18097471\n22188312\n25399565\n20582580\n22797452\n15566616\n19131954\n24331947\n11705748\n21801747\n10477521\n17293847\n15491280\n18923184\n24201173\n24762100\n11438707\n24309954\n12678851\n10638664\n12235111\n24569990\n21311042\n20190138\n19808702\n22918451",
    "results": null,
    "title": "Biodistribution and Efficacy of Targeted Pulmonary Delivery of a Protein Kinase C-\u03b4 Inhibitory Peptide: Impact on Indirect Lung Injury.",
    "xml": "<Element 'PubmedArticle' at 0x7885038cc090>"
}