INDUCING INACTIVATION OF FIBROGENIC MYOFIBROBLASTS
Provided are methods of treating fibrotic conditions in a subject and diagnostic methods for determining fibrosis and appropriate treatments for the fibrosis by the identification of specific subsets of fibrogenic myofibroblasts.
1 . A method for reducing one or more symptoms of fibrosis in a subject, comprising administering to said subject a therapeutic amount of one or more compounds that upregulate one or more of Hspa1a/b gene, PPARα, PPARγ, HSP70, HSP40, Hyaluronan synthase 1, GATA2, C/EBPa, BMPS, septin 4, Bambi, cathepsin S and H, neural proteins: synaptogyrin 1, synaptotagmin XIII, GFAP, transcription factors: Spi-C transcription factor (spi/PU.1 related), Spi-B transcription factor (spi-1/PU.related), PU.1-IRF, IRF-1 and 3 and 5, ISRE, Stat1, Pax5, Mafk2, ISGF3-g1; BL34 regulator of G-protein signaling 1, or Rnd1-Rho family GTPase, in an activated fibrogenic myofibroblast cell or fibrogenic myofibroblast-like cell in an amount sufficient to decrease or inhibit the fibrosis.
2 . The method of claim 1 wherein the one or more compounds upregulate PPARγ, PPARα and/or Hspa1a/b genes.
3 . The method of claim 1 , wherein the fibrotic condition is a fibrotic condition of the lung, liver, heart, kidney, skin, gastrointestinal tract or a combination thereof.
4 . The method according to claim 3 , wherein the fibrotic condition of the liver is chosen from fatty liver disease, steatohepatitis, primary and secondary biliary cirrhosis, cirrhosis, alcohol induced liver fibrosis, biliary duct injury, biliary fibrosis, hepatic fibrosis associated with hepatitis infection, autoimmune hepatitis, non-alcoholic fatty liver disease or progressive massive fibrosis.
5 . The method according to claim 1 , wherein the compound is selected from one or more of PPARα agonist, PPARγ agonist, Hsp70 upregulator, HSP40 upregulator, Hspa1a/b upregulator, Hyaluronan synthase 1 upregulator or GATA2 upregulator.
6 . The method according to claim 5 wherein the PPARα agonist is fenofibrate, WY14643, gemfibrozil, or ciprofibrate.
7 . The method according to claim 5 , wherein the PPARγ agonist is thiazolidinediones, or 15-deoxy-delta (12, 14)-prostaglandin J2.
8 . The method according to claim 5 , wherein the HSP70 and HSP40 upregulator is 17-allyamino-demthoxygeldanamycin.
9 . The method according to claim 5 , wherein the Hspa1a/b upregulator is taurolidine or tumor necrosis factor receptor apoptosis inducing ligand.
10 . The method according to claim 5 , wherein the PPARα agonist, or PPARγ agonist is given in combination with upregulators of HSP70, HSP40, Hspa1a/b, Hyaluronan synthase 1 or GATA2.
11 . The method according to claim 1 , wherein the compound induces inactivation of fibrogenic myofibroblasts.
12 . The method according to claim 11 , wherein the fibrogenic myofibroblast is a hepatic stellate cell.
13 . The method according to claim 1 , wherein the compound or compounds are given in combination with other antifibrotics, corticosteroids, anti-inflammatories, immunosuppressants, chemotherapeutic agents, anti-metabolites, and immunomodulators.
14 . The method according to claim 1 , wherein the compound or compounds is given in combination with one or more of adefovir dipivoxil, candesartan, colchicine, combined ATG, mycophenolate mofetil, and tacrolimus, combined cyclosporine microemulsion and tacrolimus, elastometry, everolimus, FG-3019, Fuzheng Huayu, G1262570, glycyrrhizin (monoammonium glycyrrhizinate, glycine, L-cysteine monohydrochloride, interferon gamma-1b, irbesartan, losartan, oltipraz, ORAL IMPACT®., peginterferon alfa-2a, combined peginterferon alfa-2a and ribavirin, peginterferon alfa-2b (SCH 54031), combined peginterferon alpha-2b and ribavirin, praziquantel, prazosin, raltegravir, ribavirin (REBETOL®., SCH 18908), ritonavir-boosted protease inhibitor, pentoxyphilline, tacrolimus, tauroursodeoxycholic acid, tocopherol, ursodiol, and warfarin.
15 . The method according to claim 1 , wherein the compounds or compounds are given in combination with a compound or compounds that downregulate Ssp1 and/or Pdgfc.
16 . A method for detecting hepatic stellate cells(HSCs) or portal fibroblasts (PFs) in a sample, comprising determining the presence of a marker, wherein:
a) the marker is at least one HSC marker selected from vitamin A+, Collagen+, Desmin+, GFAP+, CD146+; or
b) the marker is at least one PF marker selected from Vitamin A−, Collagen +, Thy1.1+, and Elastin+, Mesothelin+.
17 . The method according to claim 16 , wherein the methods utilize flow cytometry.
18 . A method for distinguishing portal fibroblasts (PFs) and Hepatic Stellate Cells (HSCs) in a sample, comprising at least one of
a) determining the presence of at least one HSC marker selected from vitamin A+, Collagen+, Desmin+, GFAP+, CD146+, and
b) determining the presence of at least one PF marker selected from Vitamin A−, Collagen +, Thy1.1+, and Elastin+, Mesothelin+.
19 . The method according to claim 18 , wherein the methods utilize flow cytometry.