Composition and method for reducing tissue damage from inflammatory disorder or pathogenic infection

Abstract

Compositions and methods for preventing or ameliorating tissue damage caused by an inflammatory disorder or pathogenic infections are described. In one aspect, a method for preventing or ameliorating tissue damage caused by an inflammatory disorder or pathogenic infection comprises administering to a subject a therapeutically effective amount of a neuregulin. In another aspect, the composition comprises one or more active agents that: (a) increase expression or activity of a neuregulin; (b) inhibit the expression or activity of CXCL10, STAT3 or HEME; or (c) both (a) and (b).

What is claimed is: 
     
         1 . A method for preventing or ameliorating tissue damage caused by an inflammatory disorder or pathogenic infection in a subject, comprising:
 administering to a subject in need of such treatment a composition comprising a therapeutically effective amount of a neuregulin, wherein said neuregulin is administered in a dosage range from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day.   
     
     
         2 . The method of  claim 1 , wherein said neuregulin is administered in conjunction with a secondary active agent. 
     
     
         3 . The method of  claim 2 , wherein the secondary active agent is a HEME neutralization agent, a CXCL10 inhibitor, a CXCR3 inhibitor, a STAT3 inhibitor, an anti-inflammatory agent, an antimicrobial agent or combination thereof. 
     
     
         4 . The method of  claim 2 , wherein the secondary active agent is a HEME neutralization agent. 
     
     
         5 . The method of  claim 2 , wherein the secondary active agent comprises an antibody, short interfering RNA (siRNA), aptamer, synbody, target neutralization agent, peptide, aptamer-siRNA chimera, single stranded antisense oligonucleotide, triplex forming oligonucleotide, ribozyme, external guide sequence or antagonist encoded expression vector. 
     
     
         6 . The method of  claim 1 , wherein the tissue damage is accompanied by one or more members selected from the group consisting of occlusion of vessels, blood brain barrier permeability, endothelial activation, glial activation, focal inflammation, activation of apoptosis, reversible neuronal tissue damage and irreversible neuronal tissue damage. 
     
     
         7 . The method of  claim 1 , wherein the composition is administered to the subject with a pathogenic infection. 
     
     
         8 . The method of  claim 7 , wherein the subject has malaria. 
     
     
         9 . The method of  claim 1 , wherein said inflammatory disorder or pathogenic infection is an inflammatory disease of the central or peripheral nervous system selected from the group consisting of abscess, AIDS related infections, Alzheimer's disease, chronic fatigue syndrome, congenital infections, encephalitis, ischemia/stroke, meningitis, migraine, multiple sclerosis and traumatic brain injury. 
     
     
         10 . The method of  claim 1 , wherein said inflammatory disorder or pathogenic infection is an inflammatory disease of the urogenital system selected from the group consisting of endometriosis, glomerulosclerosis, infections of the vagina and cervix, intra-amniotic infection, pelvic inflammatory disease, renal inflammation/nephritis, sexually transmitted diseases, urethritis, urinary tract infections and yeast infections. 
     
     
         11 . The method of  claim 1 , wherein said inflammatory disorder or pathogenic infection is an inflammatory disease of the digestive system selected from the group consisting of colon cancer, hepatitis, inflammatory bowel disease, interstitial cystitis, irritable bowel syndrome and ulcers. 
     
     
         12 . The method of  claim 1 , wherein said inflammatory disorder or pathogenic infection is an inflammatory disease of the respiratory system selected from the group consisting of chronic lung disease, asthma, tuberculosis and pneumonia. 
     
     
         13 . The method of  claim 1 , wherein said inflammatory disorder or pathogenic infection is an inflammatory disease of the skin, integument and/or musculoskeletal system selected from the group consisting of Behcet's Disease, Crohn's disease, dermatitis, gingivitis, gout, myalgia, osteoarthritis, periodontitis, psoriasis, rheumatoid arthritis, spondyloarthropathies and skin sunburn. 
     
     
         14 . The method of  claim 1 , wherein said inflammatory disorder or pathogenic infection is an inflammatory disease of the cardiovascular system selected from the group consisting of atherosclerosis, pericarditis, endocarditis, Kawasaki's Disease, myocarditis, rheumatic fever and vasculitis. 
     
     
         15 . The method of  claim 1 , wherein said inflammatory disorder or pathogenic infection is selected from the group consisting of autoimmune diseases, cat scratch disease, eye infections, Lyme disease, lymphadenopathy, lymphatic inflammation, opportunistic infections, radiation-induced inflammation, sarcoidosis, Sjogren's syndrome and systemic lupus erythematosus and related disorders. 
     
     
         16 . The method of  claim 1 , wherein said inflammatory disorder or pathogenic infection is caused by an infectious agent or corresponding disease selected from the group consisting of bacterial infections, sepsis, fungal infections, parasitic infections, cerebral malaria, prion protein infections, toxic compounds, nerve agents and viral infections. 
     
     
         17 . A method for preventing or ameliorating tissue damage caused by an inflammatory disorder or pathogenic infection in a subject, comprising:
 administering to said subject therapeutically effective amount(s) of one or more active agents that: (a) increase expression or activity of a neuregulin; (b) inhibit the expression or activity of CXCL10, STAT3 inhibitor or HEME neutralization agent; or (c) both (a) and (b).   
     
     
         18 . A method for enhancing the effect of anti-inflammatory therapy, comprising:
 administering to a subject who is receiving or has received anti-inflammatory therapy an effective amount of a neuregulin, wherein said neuregulin is administered in a dosage range from about 0.01 mg/kg body weightlday to about 1000 mg/kg body weightlday.   
     
     
         19 . A pharmaceutical composition, comprising:
 neuregulin;   a secondary active agent selected from the group consisting of HEME neutralization agent, CXCL10 inhibitor, CXCR3 inhibitor, STAT3 inhibitor, anti-inflammatory agent, antimicrobial agent and combinations thereof; and   a pharmaceutically acceptable carrier.   
     
     
         20 . A method for preventing or ameliorating tissue damage caused by an inflammatory disorder or pathogenic infection in a subject, comprising:
 administering into a subject in need of such treatment an effective amount of the composition of  claim 19 .   
     
     
         21 . A method for preventing or ameliorating secondary tissue damage caused by an inflammatory disorder or pathogenic infection in a subject, comprising:
 administering into a subject in need of such treatment an effective amount of a neuregulin.   
     
     
         22 . The method of  claim 21 , further comprising:
 administering into said subject a secondary active agent selected from the group consisting of HEME neutralization agent, CXCL10 inhibitor, CXCR3 inhibitor, STAT3 inhibitor, anti-inflammatory agent, antimicrobial agent and combinations thereof.   
     
     
         23 . A method for reducing mortality caused by the secondary effect of a pathogenic infection in a subject, comprising:
 administering into a subject in need of such treatment an effective amount of a neuregulin.   
     
     
         24 . The method of  claim 23 , further comprising:
 administering into said subject a secondary active agent selected from the group consisting of HEME neutralization agent, CXCL10 inhibitor, CXCR3 inhibitor, STAT3 inhibitor, anti-inflammatory agent, antimicrobial agent and combinations thereof.   
     
     
         25 . The method of  claim 23 , wherein said pathogen infection is cerebral malaria.