Mepacrine impairs neutrophil response after acute lung injury in rats. Effects on neutrophil migration.
Intraalveolar leukocytosis is integral in initiating and perpetuating airspace inflammatory reactions. We used intratracheal instillation of silica suspensions in adult male rats to cause neutrophil flux (32% increase over saline controls) without creating a protein leak, so simulating an early inflammatory response. We examined the in vivo effects of a known phospholipase A2 inhibitor (mepacrine) and the two mast cell active agents (cyproheptadine and reserpine) on lung lavage fluid chemotactic capability, alveolar macrophage (AM) production of chemotactic factor(s), and neutrophil diapedesis. Only mepacrine significantly depressed the leukocytosis (from 32% to 8% of total cells), with a similar diminution in AM chemotaxin production. Separate in vitro experiments using mepacrine-pretreated neutrophils and macrophages gave evidence that mepacrine: (1) diminishes neutrophil response to chemotaxin(s), (2) inhibits spontaneous, random neutrophil movement, and (3) diminishes macrophage-derived chemotactic factor production. These observations suggest that the earliest events in alveolar inflammatory reactions probably involve local production of chemotactic factors by AM, and that mepacrine's anti-inflammatory action results from inhibitory influences on both macrophage and neutrophil populations.
Mikes
P S
PS
Section of Pulmonary Medicine, Yale University School of Medicine, New Haven, Connecticut 06510.
Polomski
L L
LL
Gee
J B
JB
D000208:Acute Disease; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002630:Chemotactic Factors / Q000096:biosynthesis / Q000378:metabolism; D007322:Instillation, Drug; D016209:Interleukin-8; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D011796:Quinacrine / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D012822:Silicon Dioxide; D014132:Trachea
D002630:Chemotactic Factors; D016209:Interleukin-8; D012822:Silicon Dioxide; D011796:Quinacrine