Treatment and prevention of pulmonary conditions

Abstract

The invention provides compositions and methods for treating pulmonary conditions and for reducing the negative effects of pulmonary inflammation. Such compositions and methods employ protease inhibitors and a lung surfactant mixture. The compositions and methods can also include lipase inhibitors (e.g. a phospholipase inhibitors) and anti-oxidants.

1 - 131 . (canceled) 
     
     
         132 . A liquid or aerosolized composition comprising a lung surfactant polypeptide and at least anti-oxidant, wherein the lung surfactant polypeptide comprises a polypeptide having between 10-60 amino acid residues and an amino acid sequence of alternating hydrophobic and hydrophilic amino acid residue regions represented by the formula (Z a U b ) c Z d , wherein Z is a hydrophilic amino acid residue, U is a hydrophobic amino acid residue, a is an integer with an average value of 1-5, b is an integer with an average value of 3-20, c is an integer of about 1 to about 10, and d is an integer of about 0 to about 3. 
     
     
         133 . The composition of  claim 132 , wherein Z is histidine, lysine, arginine, aspartic acid, glutamic acid, 5-hydroxylysine, 4-hydroxyproline, 3-hydroxyproline, or a combination thereof. 
     
     
         134 . The composition of  claim 132 , wherein U is selected from the group consisting of valine, isoleucine, leucine, cysteine, tyrosine, phenylalanine, α-aminobutanoic acid, α-aminopentanoic acid, α-amino-2-methylpropanoic acid, α-aminohexanoic acid, or a combination thereof. 
     
     
         135 . The composition of  claim 132 , wherein U is α-aminobutanoic acid, α-aminopentanoic acid, α-amino-2-methylpropanoic acid, or α-aminohexanoic acid. 
     
     
         136 . The composition of  claim 132 , wherein the lung surfactant polypeptide comprises amino acid sequence: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 1) 
                 
                     
                   KLLLLKLLLLKLLLLKLLLLK, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 2) 
                 
                     
                   KLLLLLLLLKLLLLLLLLKLL, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 3) 
                 
                     
                   KKLLLLLLLKKLLLLLLLKKL, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 4) 
                 
                     
                   DLLLLDLLLLDLLLLDLLLLD; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 5) 
                 
                     
                   RLLLLRLLLLRLLLLRLLLLR; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 6) 
                 
                     
                   RLLLLLLLLRLLLLLLLLRLL; 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 7) 
                 
                     
                   RRLLLLLLLRRLLLLLLLRRL, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 8) 
                 
                     
                   RLLLLCLLLRLLLLCLLLR, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 9) 
                 
                     
                   RLLLLCLLLRLLLLCLLLRLL, 
                 
                     
                   or 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 10) 
                 
                     
                   RLLLLCLLLRLLLLCLLLRLLLLCLLLR. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         137 . The composition of  claim 132 , wherein the lung surfactant polypeptide is KLLLLKLLLLKLLLLKLLLLK (SEQ ID NO:1). 
     
     
         138 . The composition of  claim 132 , wherein the lung surfactant polypeptide comprises amino acid sequence SEQ ID NO: 25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28 or SEQ ID NO:29. 
     
     
         139 . The composition of  claim 132 , comprising about 0.1 to 10 percent of the lung-surfactant polypeptide. 
     
     
         140 . The composition of  claim 132 , further comprising at least one phospholipid. 
     
     
         141 . The composition of  claim 140 , wherein the phospholipid comprises dipalmitoyl phosphatidylcholine and palmitoyl, oleoyl phosphatidyl glycerol, in a mole ratio of about 4:1 to about 2:1. 
     
     
         142 . The composition of  claim 140 , wherein the phospholipid comprises about 50 to about 95 dry weight percent of the composition. 
     
     
         143 . The composition of  claim 132 , wherein the composition further comprises a spreading agent. 
     
     
         144 . The composition of  claim 143 , wherein the spreading agent is a fatty acid or fatty alcohol having a fatty acyl chain length of at least 10 carbon atoms. 
     
     
         145 . The composition of  claim 143 , wherein the spreading agent is about 2 to about 25 dry weight percent of the composition. 
     
     
         146 . The composition of  claim 143 , wherein the spreading agent further includes tyloxapol. 
     
     
         147 . The composition of  claim 132 , wherein the anti-oxidant is catalase, glutathione, N-acetylcysteine, procysteine, alpha-tocopherol, rosemary leaf extract, 2,4-diaminopyrrolo-[2,3-d]pyrimidine, ascorbic acid, leutein, zeaxanthin, cryptoxanthin, violaxanthin, carotene diol, hydroxycarotene, hydroxylycopene, alloxanthin, ebselen, dehydrocryptoxanthin or a combination thereof. 
     
     
         148 . A method for treating pulmonary inflammation in a mammal comprising administering to the mammal a therapeutically effective amount of a composition of  claim 132 . 
     
     
         149 . The method of  claim 148 , wherein the pulmonary inflammation is associated with pulmonary hypertension, neonatal pulmonary hypertension, neonatal bronchopulmonary dysplasia, chronic obstructive pulmonary disease, acute bronchitis, chronic bronchitis, emphysema, bronchiolitis, bronchiectasis, radiation pneumonitis, hypersensitivity, pneumonitis, acute inflammatory asthma, acute smoke inhalation, thermal lung injury, allergic asthma, iatrogenic asthma, cystic fibrosis, alveolar proteinosis, alpha-1-protease deficiency, pulmonary inflammatory disorders, pneumonia, acute respiratory distress syndrome, acute lung injury, idiopathic respiratory distress syndrome, or idiopathic pulmonary fibrosis. 
     
     
         150 . The method of  claim 148 , wherein the composition is administered parenterally, orally or intravenously. 
     
     
         151 . The method of  claim 148 , wherein the composition is administered by bronchoalveolar lavage, inhalation or liquid bolus administration to the lungs.