title: Anthrax lethal toxin-induced lung injury and treatment by activating MK2.
abstract: Anthrax is associated with severe vascular leak, which is caused by the bacterial lethal toxin (LeTx). Pleural effusions and pulmonary edema that occur in anthrax are believed to reflect endothelial injury caused by the anthrax toxin. Since vascular leak can also be observed consistently in rats injected intravenously with LeTx, the latter might present a simple physiologically relevant animal model of acute lung injury (ALI). Such a model could be utilized in evaluating and developing better treatment for ALI or acute respiratory distress syndrome (ARDS), as other available rodent models do not consistently produce the endothelial permeability that is a major component of ARDS. The biological activity of LeTx resides in the lethal factor metalloprotease that specifically degrades MAP kinase kinases (MKKs). Recently, we showed that LeTx inactivation of p38 MAP kinase signaling via degradation of MKK3 in pulmonary vascular endothelial cells can be linked to compromise of the endothelial permeability barrier. LeTx effects were linked specifically to blocking activation of p38 substrate and MAP kinase-activated protein kinase 2 (MAPKAPK2 or MK2) and phosphorylation of the latter's substrate, heat shock protein 27 (HSP27). We have now designed a peptide that directly and specifically activates MK2, causing HSP27 phosphorylation in cells and in vivo. The MK2-activating peptide (MK2-AP) also blocks the effects of LeTx on endothelial barriers in cultured cells and reduces LeTx-induced pulmonary vascular leak in rats. Hence, MK2-AP has the therapeutic potential to counteract anthrax or pulmonary edema and vascular leak due to other causes.
authors.affiliation: Pulmonary, Critical Care, and Sleep Division, Department of Medicine/Tupper Research Institute, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Tiegang
authors.initials: T
authors.lastname: Liu
authors.affiliation: Pulmonary, Critical Care, and Sleep Division, Department of Medicine/Tupper Research Institute, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Rod R
authors.initials: RR
authors.lastname: Warburton
authors.affiliation: Pulmonary, Critical Care, and Sleep Division, Department of Medicine/Tupper Research Institute, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Hill
authors.affiliation: Pulmonary, Critical Care, and Sleep Division, Department of Medicine/Tupper Research Institute, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts ukayyali@tuftsmedicalcenter.org.
authors.forename: Usamah S
authors.initials: US
authors.lastname: Kayyali
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D000818:Animals; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D055551:HSP27 Heat-Shock Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D034622:RNA Interference; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D020536:Enzyme Activators; D055551:HSP27 Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides; D017346:Protein Serine-Threonine Kinases; D000099190:MAP-Kinase-Activated Kinase 2; C030325:anthrax toxin
keywords: MK2; acute lung injury; endothelial; heat shock protein 27; or acute respiratory distress syndrome; permeability