POTENTIAL ROLE OF RECOMBINANT SECRETORY LEUCOPROTEASE INHIBITOR IN THE PREVENTION OF NEUTROPHIL-MEDIATED MATRIX DEGRADATION

Background - Neutrophil elastase is able to degrade connective tissue matrices and is thought to be involved in the pathogenesis of destruct ive lung diseases. Methods - The ability of recombinant secretory leuc oprotease inhibitor (rSLPI) to inhibit neutrophil mediated degradation of fibronectin in vitro is demonstrated and its efficacy compared wit h native alpha-1-proteinase inhibitor (n alpha(1)-PI), recombinant alp ha-1-proteinase inhibitor (r alpha(1)-PI), and the chemical elastase i nhibitor ICI 200 355. Results - When preincubated with neutrophils bot h rSLPI and r alpha(1)-PI were effective inhibitors of fibronectin deg radation although n alpha(1)-PI and ICI 200 355 were less effective. R ecombinant SLPI was the most effective inhibitor when the cells were a llowed to adhere to fibronectin before the addition of the inhibitors. Preincubation of rSLPI (0.1 mu mol/l) with the fibronectin plate resu lted in almost total inhibition of fibronectin degradation (reduced to 3.3 (SE 0.9)% of control), Pretreating the fibronectin plate with 1 m u mol/l rSLPI, r alpha(1)-PI and ICI 200 355 followed by thorough wash ing before the addition of cells resulted in no inhibition of fibronec tin degradation with r alpha(1)-PI and the ICI inhibitor, but rSLPI re tained its inhibitory effect. This effect could be reduced by adding r SLPI in high pH buffer or 2 mol/l NaCl. Conclusions - It is postulated that rSLPI binds to fibronectin to form a protective layer which prev ents its degradation by neutrophil elastase. It may prove to be the mo st useful therapeutic agent in the prevention of neutrophil mediated l ung damage.