Extracellular histones as biomarkers for prognosis and molecular targets for therapy

Abstract

Hyper-inflammatory responses can lead to a variety of diseases including sepsis. It is now shown that extracellular histones released in response to inflammatory challenge are mediators contributing to endothelial dysfunction, organ failure and death during sepsis. As such, they can be targeted pharmacologically by inhibitors, as well as used as biomarkers for prognosis of sepsis and other diseases.

1 . A method of inhibiting a medical condition involving extracellular histone cytotoxicity in a subject comprising administering to said subject a first inhibitor histone cytotoxicity, wherein said first inhibitor is not an H2A peptide, and wherein said condition is not systemic lupus erythematosus (SLE). 
     
     
         2 - 4 . (canceled) 
     
     
         5 . The method of  claim 1 , further comprising administering to said subject a second inhibitor of histone cytotoxicity. 
     
     
         6 . The method of  claim 5 , wherein said second inhibitor is an H1, H2A, H2B, H3 or H4 histone fragment or peptide. 
     
     
         7 . The method of  claim 6 , further comprising administering to said subject a cocktail of at least three distinct histone fragments or peptides. 
     
     
         8 . The method of  claim 1 , wherein said subject is a human, dog, cat, horse, monkey, mouse, rat, rabbit, sheep, goat, cow or pig. 
     
     
         9 . The method of  claim 1 , further comprising administering to said subject an anti-inflammatory agent. 
     
     
         10 . The method of  claim 1 , further comprising administering to said subject activated protein C. 
     
     
         11 - 15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein said medical condition is bacterial sepsis, fungal sepsis, surgery, traumatic hemorrhage and/or tissue damage, acute pancreatitis, acute respiratory distress syndrome, ischemia-reperfusion injury, cardiovascular disease, autoimmune disease other than SLE, chemotherapy toxicity, radiotherapy toxicity, cytokine therapy toxicity, or burn. 
     
     
         17 . A method of inhibiting a non-septic medical condition involving extracellular histone cytotoxicity in a subject comprising administering to a subject a first inhibitor histone cytotoxicity, and wherein said condition is not systemic lupus erythematosus (SLE). 
     
     
         18 - 25 . (canceled) 
     
     
         26 . A method of inhibiting pro-inflammatory cytokine production by endothelial cells in a subject comprising administering to said subject a first inhibitor histone cytotoxicity, wherein said first inhibitor is not an H2A peptide. 
     
     
         27 . The method of  claim 26 , wherein said subject does not have systemic lupus erythematosus (SLE). 
     
     
         28 . The method of  claim 26 , wherein said pro-inflammatory cytokine is IL-6 or IL-8. 
     
     
         29 - 31 . (canceled) 
     
     
         32 . The method of  claim 26 , further comprising administering to said subject a second inhibitor of histone cytotoxicity. 
     
     
         33 . The method of  claim 32 , wherein said second inhibitor is an H1, H2A, H2B, H3 or H4 histone fragment or peptide. 
     
     
         34 . The method of  claim 33 , further comprising administering to said subject a cocktail of at least three distinct histone fragments or peptides. 
     
     
         35 . The method of  claim 26 , wherein said subject is a human, dog, cat, horse, monkey, mouse, rat, rabbit, sheep, goat, cow or pig. 
     
     
         36 - 39 . (canceled) 
     
     
         40 . The method of  claim 26 , wherein said subject suffers from a chronic cardiovascular disease, athlerosclereosis, tumor angiogenesis or trauma. 
     
     
         41 . A method of reducing endothelial permeability in a subject comprising administering to said subject a first inhibitor histone cytotoxicity, wherein said first inhibitor is not an H2A peptide. 
     
     
         42 . The method of  claim 41 , and wherein said subject does not have systemic lupus erythematosus (SLE). 
     
     
         43 . The method of  claim 41 , wherein said subject has contacted anthrax or suffers from trauma, edema, vascular leak or circulatory shock. 
     
     
         44 - 46 . (canceled) 
     
     
         47 . The method of  claim 41 , further comprising administering to said subject a second inhibitor of histone cytotoxicity. 
     
     
         48 . The method of  claim 47 , wherein said second inhibitor is an H1, H2A, H2B, H3 or H4 histone fragment or peptide. 
     
     
         49 . The method of  claim 48 , further comprising administering to said subject a cocktail of at least three distinct histone fragments or peptides. 
     
     
         50 . The method of  claim 41 , wherein said subject is a human, dog, cat, horse, monkey, mouse, rat, rabbit, sheep, goat, cow or pig. 
     
     
         51 - 54 . (canceled)