Inhibition of pulmonary fibrosis with nutlin-3A and peptides
In fibrotic lung fibroblasts, basal levels of p53 protein (and miR-34a) are markedly suppressed, leading to reduced p53-mediated inhibition of uPA and uPAR, or concurrent induction of PAI-1. These changes contribute to excessive FL-fibroblast proliferation and production of extracellular matrix (ECM), and, therefore, pulmonary fibrosis. These processes are reversed by treating the cells, and treating subjects suffering from idiopathic pulmonary fibrosis (IPF) with the small organic molecule nutlin-3a (NTL) or with a peptide, CSP-4 (SEQ ID NO:1), or variants or derivatives or multimers of this peptide, which increase p53 levels by inhibiting MDM2-mediated degradation of p53 protein. Use of these compounds serves as a new approach to the treatment of IPF, as they restore p53 expression and p53-mediated changes in the uPA-fibrinolytic system in FL-fibroblasts and restrict production and deposition of ECM.
1. A method of reducing fibrosis or acute lung injury in a subject in need thereof, comprising administering to the subject an effective amount of a polypeptide consisting of:
(a) FTTFTVT (SEQ ID NO: 1); and
(b) 1-5 amino acids on the N- and/or C-terminus of FTTFTVT (SEQ ID NO: 1), or
a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the fibrosis is pulmonary fibrosis.
3. The method of claim 1 , wherein the fibrosis is idiopathic pulmonary fibrosis.
4. The method of claim 1 , wherein the polypeptide is administered by instillation into the lungs of the subject.
5. The method of claim 1 , wherein the polypeptide is administered intranasally or intrabronchially to the subject.
6. A method of reducing or inhibiting proliferation of fibroblasts in a subject in need thereof, comprising administering to the subject an effective amount of a polypeptide consisting of:
(a) an amino acid sequence of FTTFTVT (SEQ ID NO: 1); and
(b) 1-5 amino acids on the N- and/or C-terminus of FTTFTVT (SEQ ID NO: 1), or
a pharmaceutically acceptable salt thereof.
7. The method of claim 6 , wherein the fibroblasts are lung fibroblasts.
8. The method of claim 6 , wherein the fibroblasts are fibrotic lung fibroblasts.
9. The method of claim 6 , wherein the subject has pulmonary fibrosis.
10. The method of claim 6 , wherein the subject has idiopathic pulmonary fibrosis.
11. The method of claim 6 , wherein the polypeptide is administered by instillation into the lungs of the subject.
12. The method of claim 6 , wherein the polypeptide is administered intranasally or intrabronchially to the subject.
13. A method of treating a subject having a disease or condition characterized by fibrosis, comprising administering to the subject a polypeptide consisting of:
(a) FTTFTVT (SEQ ID NO: 1); and
(b) 1-5 amino acids on the N- and/or C-terminus of FTTFTVT (SEQ ID NO: 1), or
a pharmaceutically acceptable salt thereof;
wherein the polypeptide is administered at a dose of about 0.2 mg/kg to about 250 mg/kg.
14. The method of claim 13 , wherein the dose is about 0.2 mg/kg to about 50 mg/kg.
15. The method of claim 13 , wherein the disease or the condition is pulmonary fibrosis.
16. The method of claim 13 , wherein the disease or the condition is idiopathic pulmonary fibrosis.
17. The method of claim 13 , wherein the polypeptide is administered by instillation into the lungs of the subject.
18. The method of claim 13 , wherein the polypeptide is administered intranasally or intrabronchially to the subject.