Compositions and methods for the treatment of tissue fibrosis
Provided are methods of treating tissue fibrosis comprising administering to a subject in need of treatment an effective amount of an agent that inhibits a hyaluron synthase (HAS) or CD44. Further provided are methods of inhibiting myofibroblast invasion, or of reducing matrix deposition in the lung, the methods comprising administering to a subject in need of treatment an effective amount of an agent that inhibits a HAS or CD44. Further provided are methods of determining the progression of pulmonary fibrosis, the methods comprising determining the level of matrix metalloproteinase expression in a cell, and comparing the level of expression to that of a control cell, wherein an increased level of expression relative to the control cell indicates progression of the disease.
1. A method of targeting an invasive fibroblast phenotype and treating pulmonary fibrosis comprising formation of excess fibrous connective tissue in the lung and accumulation of myofibroblasts comprising the invasive fibroblast phenotype that invade extracellular matrix of the lung in a subject, the method comprising:
administering to the subject a pharmaceutical composition comprising a therapeutic amount of an siRNA HAS2 inhibitor targeting a region selected from 1530-1550 nt, 1051-1071 nt, 1424-1444 nt, and 1777-1797 nt of SEQ ID NO. 20,
wherein the therapeutic amount reduces collagen and the formation of excess fibrous connective tissue in the lung, reduces accumulation of myofibroblasts comprising the invasive fibroblast phenotype that invade extracellular matrix of the lung, and alters expression in the invasive fibroblast phenotype characterized by one or more of: up-regulation of MMP-9, up-regulation of MMP-12, up-regulation of MMP-14, down-regulation of TIMP3, and down-regulation of ADAMTS1, relative to an untreated control.
2. The method of claim 1 , wherein the pharmaceutical composition inhibits the biological activity of HAS2.
3. The method of claim 1 , wherein the pharmaceutical composition inhibits the biological activity of CD44.
4. The method of claim 1 , wherein the pharmaceutical composition further comprises an antibody.
5. The method of claim 1 , wherein the biological activity of both HAS2 and CD44 are reduced.
6. The method of claim 1 , wherein the siRNA HAS2 inhibitor comprises a nucleotide sequence of SEQ ID NO. 15.