ABSTRACT
The balance between proteases and antiproteases in the lower respiratory tract is believed to play a role in the outcome of interstitial lung diseases. In this cross-sectional study, we measure several phagocyte derived enzymes, namely plasminogen activator, neutrophil elastase and an ill-defined protease active on the trialanine chromophore substrate succinyl-alanine3-nitroanilide (SLAPN) in bronchoalveolar lavage (BAL) fluid from 42 patients with pulmonary sarcoidosis and from 43 patients with collagen vascular disease (CVD), 22 without lung disease (group I) and 21 associated with parenchymal lung disease (group II). The results show: a) that sarcoidosis is associated with increased plasminogen activator activity and with the presence of enzymatic activity against SLAPN corresponding at least in part to a metalloprotease; b) that CVD in the absence of radiographic lung disease is associated with an increase of plasminogen activator activity and increased levels of alpha 1-antiprotease-neutrophil elastase complexes; c) that the majority of untreated CVD (group II) patients have detectable levels of neutrophil elastase activity. These data show that patients with pulmonary sarcoidosis and CVD have different enzymatic profiles in their lower respiratory tract as assessed by BAL. Thus, sarcoidosis (mostly lymphocytic) is associated with enhanced macrophage-derived proteolytic activity in BAL, while CVD patients both with and without lung disease have increased neutrophil counts and neutrophil elastase complexed to alpha 1-protease inhibitor and presumably inactive in BAL. Finally, only BAL from untreated CVD patients with interstitial lung disease contain neutrophil elastase activity. This latter activity could contribute to the lung lesions frequently observed in these disorders.
Subject(s)
Bronchoalveolar Lavage Fluid/metabolism , Collagen Diseases/enzymology , Peptide Hydrolases/metabolism , Phagocytes/enzymology , Sarcoidosis/enzymology , Vascular Diseases/enzymology , Adult , Aged , Cross-Sectional Studies , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Neutrophils/enzymology , Oligopeptides/metabolism , Pancreatic Elastase/metabolism , Plasminogen Activators/metabolism , Plasminogen Activators/physiology , Protease Inhibitors/metabolism , Serum Albumin/metabolismABSTRACT
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.
Subject(s)
Lung Diseases/physiopathology , Neutrophils/drug effects , Quinacrine/pharmacology , Acute Disease , Animals , Cell Movement/drug effects , Chemotactic Factors/biosynthesis , Chemotactic Factors/metabolism , Instillation, Drug , Interleukin-8 , Lung Diseases/chemically induced , Lung Diseases/pathology , Male , Mast Cells/metabolism , Neutrophils/physiology , Rats , Rats, Inbred F344 , Silicon Dioxide , TracheaABSTRACT
We describe some features of neutrophil migration and their defense or injury mechanism in the lung. Employing an intratracheal silica instillation model in rats, we examined the effects on the silica-induced neutrophil migration of mepacrine, colchicine and reserpine on such migration in vivo and of mepacrine on phorbol-stimulated elastase release and superoxide anion generation by human neutrophils in vitro. Mepacrine sharply diminished neutrophil migration, O2 and elastase release. Colchicine produced variable effects on neutrophil migration which was unaffected by the mast cell agent reserpine. The implications for lung injury and therapy are discussed.
