Search for drugs that may reduce the load of neutrophil azurophilic granule enzymes in the lungs of patients with emphysema.
Neutrophil elastase and myeloperoxidase probably play an important role in the development of pulmonary emphysema. We have analyzed drugs from the major classes of agents that alter neutrophil function to determine if there are drugs in use today that can reduce the load of neutrophil elastase or myeloperoxidase in the lungs of smokers. Eleven representative drugs were tested for their ability to inhibit chemotaxis and degranulation. None of the drugs inhibited chemotaxis in a dose-response fashion at concentrations achievable in human plasma. Sulfinpyrazone, phenylbutazone, and auranofin completely inhibited the release of azurophilic granules (myeloperoxidase) and tertiary granules (beta-D-glucuronidase) when formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) was used as the stimulant, and inhibited azurophilic granule release by 69%, 19%, and 64% respectively, but not tertiary granule release when macrophage-conditioned media was used as the stimulus. In conclusion, none of the drugs tested are inhibitors of chemotaxis; however, three are excellent inhibitors of azurophilic granule enzyme release. Of these three, sulfinpyrazone, a drug that is not currently used clinically for its antiinflammatory effects, is the least toxic and should be considered as a potential drug to reduce the elastase and myeloperoxidase load in the lungs of smokers who are developing emphysema.
Stevens
M D
MD
Department of Biochemistry, University of Texas Health Center, Tyler 75710.
Miller
E J
EJ
Cohen
A B
AB
D000893:Anti-Inflammatory Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D002633:Chemotaxis / Q000187:drug effects*; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology*; D009195:Peroxidase / Q000378:metabolism*; D011656:Pulmonary Emphysema / Q000188:drug therapy* / Q000201:enzymology; D013442:Sulfinpyrazone / Q000494:pharmacology / Q000627:therapeutic use*
D000893:Anti-Inflammatory Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D009195:Peroxidase; D005966:Glucuronidase; D013442:Sulfinpyrazone