Dilute surfactant or isolated surfactant protein solution for the reduction of surface tension in the lung

Abstract

In permeability lung edema, cardiogenic lung edema or neonatal respiratory distress, there is heterogeneous liquid distribution throughout the lungs. The excess alveolar liquid reduces gas exchange. Mechanical ventilation is used to improve gas exchange. In the presence of heterogeneous liquid distribution, there are surface tension-dependent stress concentrations in septa separating aerated from flooded alveoli. Mechanical ventilation, by inflating the lung above normal volumes, thus increasing surface tension above normal, exacerbates the stress concentrations and consequently injures, or exacerbates pre-existing injury of, the alveolar-capillary barrier. Any means of lowering surface tension should lessen ventilation injury of the lung. In the present invention, dilute exogenous surfactant solution or surfactant protein C solution interacts with albumin to lower surface tension, likely through effective promotion of surfactant lipid adsorption. Dilute surfactant or SP-C solution could be administered via either the trachea or the vasculature. Either solution could be delivered in the absence or presence of albumin or alternative facilitating solute, to lower surface tension and lessen ventilation injury of the heterogeneously flooded lung.

1 . A method of reducing ventilation injury to a patient whose lung has regions with heterogeneous alveolar flooding by alveolar liquid, said method comprising the step of (i) delivering to the patient a solution comprising a predetermined amount of a surfactant protein C, wherein said predetermined amount of said surfactant protein C is selected to provide a concentration of said surfactant protein C in the alveolar liquid in a range of from 0.000001 weight/volume percent to 1 weight/volume percent after the performance of step (i), and wherein a negatively-charged solute is present in the alveolar liquid in a concentration which is in a range of from greater than 2 weight/volume percent to less than 12 weight/volume percent after the performance of step (i), said weight/volume percents of said surfactant protein C and said negatively-charged solute being based on the total volume of the alveolar liquid after the performance of step (i). 
     
     
         2 . The method of  claim 1 , wherein said negatively-charged solute comprises at least one chemical selected from the group consisting of albumin, fibrinogen and negatively-charged dextran. 
     
     
         3 . The method of  claim 1 , wherein said surfactant protein C is natural, recombinant, or synthetic. 
     
     
         4 . The method of  claim 3 , wherein said surfactant protein C is synthetic and selected from sSP-Css-ion lock, sSP-Css-ion sSP-Cff-leuc, and combinations thereof. 
     
     
         5 . The method of  claim 1 , wherein said concentration of said surfactant protein Cin the alveolar liquid after the performance of step (i) is in a range of from 0.0005 weight/volume percent to 1 weight/volume percent. 
     
     
         6 . The method of  claim 1 , wherein said concentration of said surfactant protein C the alveolar liquid after the performance of step (i) is in a range of from 0.00001 weight/volume percent to 1 weight/volume percent. 
     
     
         7 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.00001 weight/volume percent to 0.1 weightivolunie percent. 
     
     
         8 . The method of  claim 1 , wherein said negatively-charged solute is present in the alveolar liquid in a concentration which is in a range of from 2.1 weight/volume percent to 11 weight/volume percent after the performance of step (i). 
     
     
         9 . The method of  claim 1 , wherein said surfactant protein C is derived from an animal. 
     
     
         10 . The method of  claim 1  wherein said solution comprises a surfactant containing said surfactant protein C. 
     
     
         11 . The method of  claim 1 , wherein said solution further comprises lipids. 
     
     
         12 . The method of  claim 1 , wherein said alveolar liquid is contained in a patient's alveoli, said alveolar liquid having a surface tension which is lowered by the performance of step (i) such that the lowered surface tension of the alveolar liquid lessens ventilation-induced overdistension injury of the patient's lung. 
     
     
         13 . The method of  claim 12 , wherein the lowered surface tension of the alveolar liquid reduces stress concentrations in the patient's lung. 
     
     
         14 . The method of  claim 13 , wherein the patient's alveoli are flooded to substantially the same extent. 
     
     
         15 . The method of  claim 13 , wherein the patient's alveoli are heterogeneously flooded, whereby the lowered surface tension of the alveolar liquid lessens ventilation-induced overdistension injury of intervening septa located between aerated and flooded alveoli. 
     
     
         16 . The method of  claim 1 , wherein step (i) comprises the step of administering said solution comprising said surfactant protein C to a trachea or bronchus of the patient having the lung. 
     
     
         17 . The method of  claim 1 , wherein some of said negatively-charged solute is already present in the alveolar liquid and some of said negatively-charged solute is delivered as part of said solution. 
     
     
         18 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.00001 weight/volume % to 0.1 weight/volume percent. 
     
     
         19 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0005 weight/volume percent to 0.05 weight/volume percent. 
     
     
         20 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.00001 weight/volume percent to 0.05 weight/volume percent. 
     
     
         21 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0001 weight/volume percent to 0.05 weight/volume percent. 
     
     
         22 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.005 weight/volume percent to 0.05 weight/volume percent. 
     
     
         23 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0025 weight/volume percent to 0.05 weight/volume percent. 
     
     
         24 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.00001 weight/volume percent to 0.01 weight/volume percent. 
     
     
         25 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0005 weight/volume percent to 0.01 weight/volume percent. 
     
     
         26 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0001 weight/volume percent to 0.01 weight/volume percent. 
     
     
         27 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.005 weight/volume percent to 0.01 weight/volume percent. 
     
     
         28 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0025 weight/volume percent to 0.01 weight/volume percent. 
     
     
         29 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0005 weight/volume percent to 0.1 weight/volume percent. 
     
     
         30 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0001 weight/volume percent to 0.1 weight/volume percent. 
     
     
         31 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.005 weight/volume percent to 0.1 weight/volume percent. 
     
     
         32 . The method of  claim 1 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0025 weight/volume percent to 0.1 weight/volume percent. 
     
     
         33 . The method of  claim 1 , wherein step (i) is performed by injecting said solution into a circulatory system of a patient having the lung. 
     
     
         34 . A method of reducing ventilation injury to a patient whose lung has regions with heterogeneous alveolar flooding by alveolar liquid which contains a negatively-charged solute, said method comprising the step of (i) delivering to the patient a solution comprising a predetermined amount of a surfactant protein C and no additional negatively-charged solute, wherein said predetermined amount of said surfactant protein C is selected to provide a concentration of said surfactant protein C in the alveolar liquid in a range of from 0.000001 weight/volume percent to 1 weight/volume percent after the performance of step (i), and wherein the negatively-charged solute is present in the alveolar liquid in a concentration which is in a range of from greater than 2 weight/volume percent to less than 12 weight/volume percent after the performance of step (i), said weight/volume percents of said surfactant protein C and said negatively-charged solute being based on the total volume of the alveolar liquid after the performance of step (i). 
     
     
         35 . The method of  claim 34 , wherein said negatively-charged solute comprises at least one chemical selected from the group consisting of albumin, fibrinogen and negatively-charged dextran. 
     
     
         36 . The method of  claim 34 , wherein said surfactant protein C is natural, recombinant, or synthetic. 
     
     
         37 . The method of  claim 36 , wherein said surfactant protein C is synthetic and selected from sSP-Css-ion lock, sSP-Css-ion lock B sSP-Cff-leuc, and combinations thereof. 
     
     
         38 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0005 weight/volume percent to 1 weight/volume percent. 
     
     
         39 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.00001 weight/volume percent to 1 weight/volume percent. 
     
     
         40 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.00001 weight/volume percent to 0.1 weight/volume percent. 
     
     
         41 . The method of  claim 34 , wherein said negatively-charged solute is present in the alveolar liquid in a concentration which is in a range of from 2.1 weight/volume percent to 11 weight/volume percent after the performance of step (i). 
     
     
         42 . The method of  claim 34 , wherein said surfactant protein C is derived from an animal. 
     
     
         43 . The method of  claim 34 , wherein said solution comprises a surfactant containing said surfactant protein C. 
     
     
         44 . The method of  claim 34 , wherein said solution further comprises lipids. 
     
     
         45 . The method of  claim 34 , wherein said alveolar liquid is contained in a patient's alveoli, said alveolar liquid having a surface tension which is lowered by the performance of step (i) such that the lowered surface tension of the alveolar liquid lessens ventilation-induced overdistension injury of the patient's lung. 
     
     
         46 . The method of  claim 45 , wherein the lowered surface tension of the alveolar liquid reduces stress concentrations in the patient's lung. 
     
     
         47 . The method of  claim 46 , wherein the patient's alveoli are flooded to substantially the same extent. 
     
     
         48 . The method of  claim 46 , wherein the patient's alveoli are heterogeneously flooded, whereby the lowered surface tension of the alveolar liquid lessens ventilation-induced overdistension injury of intervening septa located between aerated and flooded alveoli 
     
     
         49 . The method of  claim 34 , wherein step (i) comprises the step of administering said solution comprising said surfactant protein C to a trachea or bronchus of the patient having the king. 
     
     
         50 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.00001 weight/volume % to 0.1 weight/volume percent. 
     
     
         51 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0005 weight/volume percent to 0.05 weight/volume percent. 
     
     
         52 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.00001 weight/volume percent to 0.05 weight/volume percent. 
     
     
         53 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0001 weight/volume percent to 0.05 weight/volume percent. 
     
     
         54 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.005 weight/volume percent to 0.05 weight/volume percent. 
     
     
         55 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0025 weight/volume percent to 0.05 weight/volume percent. 
     
     
         56 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.00001 weight/volume percent to 0.01 weight/volume percent. 
     
     
         57 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0005 weight/volume percent to 0.01 weight/volume percent. 
     
     
         58 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0001 weight/volume percent to 0.01 weight/volume percent. 
     
     
         59 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.005 weight/volume percent to 0.01 weight/volume percent. 
     
     
         60 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0025 weight/volume percent to 0.01 weight/volume percent. 
     
     
         61 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0005 weight/volume percent to 0.1 weight/volume percent. 
     
     
         62 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0001 weight/volume percent to 0.1 weight/volume percent. 
     
     
         63 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.005 weight/volume percent to 0.1 weight/volume percent. 
     
     
         64 . The method of  claim 34 , wherein said concentration of said surfactant protein C in the alveolar liquid after the performance of step (i) is in a range of from 0.0025 weight/volume percent to 0.1 weight/volume percent. 
     
     
         65 . The method of  claim 34 , wherein step (i) is performed by injecting said solution into a circulatory system of a patient having the lung.