Use of parathyroid hormone-related protein (PTHrP) in the diagnosis and treatment of chronic lung disease and other pathologies

Abstract

This invention pertains to the discovery that Parathyroid Hormone-related Protein (PTHrP) can be detect and/or stage, and/or treat chronic lung diseases. In particular, it was discovered that PTHrP levels in broncho-alveolar lavage are indicative of lung “health” and “disease, and can be used to predict lung disease in patients at risk of chronic lung disease and/or to evaluate the efficacy of a ventilation regime.

1 . A method of inhibiting lipofibroblast to myofibroblasts transdifferentiation in a mammal, said method comprising: 
 administering to said mammal a PPAR gamma ligand in a concentration sufficient to partially or fully inhibit lipofibroblast to myofibroblast transdifferentiation in said mammal when said mammal is exposed to a hyperoxic condition.    
     
     
         2 . The method of  claim 1 , wherein said PPAR gamma ligand is a thiozolidinedione (TZD).  
     
     
         3 . The method of  claim 1 , wherein said PPAR gamma ligand is selected from the group consisting of rosiglitazone, troglitazone (Resulin), farglitazar, phenylacetic acid, GW590735, GW677954, Avandia, Avandamet (avandia+metformin), ciglitazone, 15 deoxy prostaglandin J2 (15PGJ2), 15-deoxy-delta12,14 PGJ2, GW-9662, and MCC-555.  
     
     
         4 . The method of  claim 1 , wherein said PPAR gamma ligand is rosiglitazone or an analogue thereof.  
     
     
         5 . The method of  claim 1 , wherein said PPAR gamma ligand is administered in a concentration of at least 0.5 mg/kg.  
     
     
         6 . The method of  claim 1 , wherein said PPAR gamma ligand is administered in a concentration of at least 1 mg/kg.  
     
     
         7 . The method of  claim 1 , wherein said mammal is a non-human mammal.  
     
     
         8 . The method of  claim 1 , wherein said mammal is a human.  
     
     
         9 . The method of  claim 1 , wherein said mammal is a human having or at risk for bronchopulmonary dysplasia.  
     
     
         10 . A method of mitigating one or more symptoms of a condition characterized by transdifferentiation of lipofibroblasts to myofibroblasts in a mammal, said method comprising: 
 administering to said mammal a PPAR gamma ligand in a concentration sufficient to partially or fully inhibit lipofibroblast to myofibroblast transdifferentiation in said mammal.    
     
     
         11 . The method of  claim 10 , wherein said PPAR gamma ligand is a thiozolidinedione (TZD).  
     
     
         12 . The method of  claim 10 , wherein said PPAR gamma ligand is selected from the group consisting of rosiglitazone, troglitazone (Resulin), farglitazar, phenylacetic acid, GW590735, GW677954, Avandia, Avandamet (avandia+metformin), ciglitazone, 15 deoxy prostaglandin J2 (15PGJ2), 15-deoxy-delta12,14 PGJ2, GW-9662, and MCC-555.  
     
     
         13 . The method of  claim 10 , wherein said PPAR gamma ligand is rosiglitazone or an analogue thereof.  
     
     
         14 . The method of  claim 10 , wherein said PPAR gamma ligand is administered in a concentration of at least 0.5 mg/kg.  
     
     
         15 . The method of  claim 10 , wherein said PPAR gamma ligand is administered in a concentration of at least 1 mg/kg.  
     
     
         16 . The method of  claim 10 , wherein said mammal is a non-human mammal.  
     
     
         17 . The method of  claim 10 , wherein said mammal is a human.  
     
     
         18 . The method of  claim 10 , wherein said mammal is a human having or at risk for bronchopulmonary dysplasia.  
     
     
         19 . The method of  claim 10 , wherein said condition is selected from the group consisting of a fibrosis, scleroderma, periodontal disease, endometriosis, pancreatic disease, chronic lung disease, acute lung disease, and obesity related lung disease.  
     
     
         20 . The method of  claim 10 , wherein said condition is bronchopulmonary dysplasia.  
     
     
         21 . A kit for mitigating one or more symptoms of a condition characterized by transdifferentiation of lipofibroblasts to myofibroblasts in a mammal, said kit comprising: 
 a PPAR gamma ligand; and    instructional materials teaching the use of a PPAR gamma ligand to inhibit the transdifferentiation of lipofibroblasts to myofibroblasts in vivo.    
     
     
         22 - 23 . (canceled)  
     
     
         24 . A method of mitigating one or more symptoms of a condition characterized by transdifferentiation of lipofibroblasts to myofibroblasts in a mammal, said method comprising: 
 administering to said mammal an agent that:    inhibits downregulation of one or more components selected from the group consisting of PPARgamma, ADRP, PTHrPR, and CP-CYT in a mammal exposed to hyperoxic conditions; and/or that inhibits upregulation of alpha SMA in a mammal exposed to hyperoxic conditions.    
     
     
         25 - 27 . (canceled)  
     
     
         28 . A method of screening for an agent that mitigates one or more symptoms of a condition characterized by transdifferentiation of lipofibroblasts to myofibroblasts in a mammal, said method comprising: 
 exposing a test mammal to hyperoxic conditions;    administering a test agent to said mammal; and    determining the expression of one or more components selected from the group consisting of PPARgamma, ADRP, PTHrPR, CP-CYT, and alpha SMA wherein inhibition of the hyperoxic-induced downregulation of one or more components selected from the group consisting of PPARgamma, ADRP, PTHrPR, and CP-CYT in a mammal exposed to hyperoxic conditions; and/or inhibition of the hyperoxic-induced upregulation of alpha SMA in said test mammal indicates that said test agent is a good candidate agent for the mitigation of one or more symptoms of a condition characterized by transdifferentiation of lipofibroblasts to myofibroblasts in a mammal.    
     
     
         29 . The method of  claim 28  where said determining the expression comprises measuring mRNA or protein expression of one or more components selected from the group consisting of PPARgamma, ADRP, PTHrPR, CP-CYT, and alpha SMA.  
     
     
         30 . A method of evaluating the progression of a chronic lung disease in a mammal, said method comprising: 
 providing a sample comprising a fluid, cell, or tissue from the lung, trachea, or bronchi of said mammal; and    measuring the level of parathyroid hormone related protein (PTHrP) where a lower level of PTHrP, as compared to the level found in a comparable sample from a normal healthy mammal indicates an increase in severity or progression of said lung disease.    
     
     
         31 - 43 . (canceled)  
     
     
         44 . A method of evaluating the efficacy of a therapeutic regimen for the prevention or treatment of a chronic lung disease, said method comprising: 
 providing a sample comprising a fluid, cell, or tissue from the lung or bronchi of said mammal; and    measuring the level of parathyroid hormone related protein (PTHrP) where a level of PTHrP, compared to the level found is a comparable sample from a normal healthy mammal indicates efficacy of said therapeutic regimen and a level of PTHrP lower than the level found in a comparable sample from a normal healthy mammal indicates that the therapeutic regimen is of lower efficacy.    
     
     
         45 . A method of screening for an agent that mitigate one or more symptoms of lung disease, said method comprising: 
 contacting a cell or tissue with said test agent; and    detecting a change in expression of PTHrP or PTHrP receptor, where a decrease in expression or activity of PTHrP or PTHrP receptor indicates that said test agent mitigates one or more symptoms of lung disease.    
     
     
         46 - 47 . (canceled)  
     
     
         48 . A method of screening for an agent that mitigates one or more symptoms of a pathology characterized by transdifferentiation of a mesodermal cell, said method comprising: 
 contacting a cell or tissue with said test agent; and    detecting a change in expression of PTHrP or PTHrP receptor, where a decrease in expression or activity of PTHrP or PTHrP receptor indicates that said test agent mitigates one or more symptoms of said pathology.    
     
     
         49 - 50 . (canceled)  
     
     
         51 . A method of screening for an agent that mitigates one or more symptoms of a pathology selected from the group consisting of glial scarring, scleroderma, periodontal disease, osteoporosis, post-partum bladder disease, arthritis, pancreatic disease, and stroke, said method comprising: 
 contacting a cell or tissue with said test agent; and    detecting a change in expression of PTHrP or PTHrP receptor, where a decrease in expression or activity of PTHrP or PTHrP receptor indicates that said test agent mitigates one or more symptoms of said pathology.    
     
     
         52 - 69 . (canceled)  
     
     
         70 . A method of prescreening for an agent that modulates one or more symptoms associated with a pathology selected from the group consisting of chronic lung disease, acute lung disease, obesity related lung disease, fibrosis, hypertension, glial scarring, restenosis, osteoporosis, scleroderma, arthritis, pancreatic disease, and stroke, said method comprising: 
 contacting a test agent with a PTHrP or a PTHrP receptor or with a nucleic acid that encodes a PTHrP or a PTHrP receptor; and    detecting specific binding of said test agent to said PTHrP or a PTHrP receptor or to said nucleic acid that encodes a PTHrP or a PTHrP receptor; wherein specific binding indicates that said test agent is a good candidate for an agent that modulates one or more symptoms of said pathology.    
     
     
         71 - 81 . (canceled)  
     
     
         82 . A method of mitigating a symptom associated with a chronic lung disease in a mammal, said method comprising: 
 increasing the level of parathyroid hormone related protein (PTHrP) in the lung tissue of said mammal, or increasing the expression of PTHrP receptors in the lung tissue of said mammal, or mimicking the effects of increased PTHrP expression or activity downstream in a PTHrP-regulated pathway.    
     
     
         83 - 84 . (canceled)  
     
     
         85 . A method of altering the amplitude and/or frequency of uterine contractions, said method comprising: 
 increasing PTHrP expression or activity of PTHrP or the expression or activity of a PTHrP receptor to decrease the amplitude and/or frequency of uterine contractions.    
     
     
         86 . The method of  claim 85 , wherein said increasing comprising administering PTHrP or an analogue thereof.  
     
     
         87 . A method of mitigating a symptom associated with a pathology selected from the group consisting of hepatic fibrosis, kidney fibrosis, cerebrovascular incident, skin fibrosis, scleroderma, gingival diseases, endometriosis, bladder epithelial hypertrophy, bladder disease, incontinence, overactive bladder, arthritis, and immaturity of the mesoderm in preterm infants, said method comprising: 
 increasing the level of parathyroid hormone related protein (PTHrP), or increasing the expression of PTHrP receptors in the mammal, or mimicking the effects of increased PTHrP expression or activity downstream in a PTHrP-regulated pathway.    
     
     
         88 . A method of monitoring and/or evaluating a ventilation regime in a mammal on a respirator, said method comprising: 
 providing a biological sample comprising a fluid, cell, or tissue from the lung, trachea, or bronchi of said mammal; and    measuring the level of parathyroid hormone related protein (PTHrP) where a lower level of PTHrP, as compared to the level found in a comparable sample from a normal healthy mammal indicates that said ventilation regime is suboptimal.    
     
     
         89 - 101 . (canceled)  
     
     
         102 . A kit for monitoring and/or evaluating a ventilation regime in a mammal on a respirator, said kit comprising: 
 one or more reagents for determining PTHrP levels in a biological sample obtained from said mammal.    
     
     
         103 - 107 . (canceled)