Roles of endothelins and their receptors in immune complex-induced polymorphonuclear-mediated lung injury (reversed passive Arthus reaction) in CD-1 mice

A number of pro-inflammatory mediators (leukotrienes, platelet activating factor, cytokines) participate in the process of neutrophil-dependent lung injury induced by immune complexes. Here, we studied the role of endothelins (ET) in the reversed passive Arthus reaction (AR) as a model of pneumonitis in CD-1 mice. We examined the broncholaveolar lavage fluid (BALF) for signs of inflammation such as the accumulation of cells, myeloperoxidase (MPO) activity and hemoglobin (Hb) levels, as a measure of hemorrhagic lesions, 24 h after injection. We used a selective ETA (BQ-123) or a non-selective ETA/ETB-R (SB 209670) receptor antagonist at various concentrations (2.5, 5 or 10 mg/kg ip at -8, 0, 8 and 16 h) to assess the involvement of ET. Challenged mice revealed signs of acute inflammation and hemorrhagic lesions. Levels of Hb and MPO, total and neutrophil cell counts increased by 9-, 9-, 3.2- and 63-fold, respectively. The lower dose of SE 209670 reduced Hb levels by 21% (P<0.05), without affecting cell accumulation or MPO. The mid-dose had no effect; the highest dose caused 60, 57 and 70% increases in Hb levels, total cell and neutrophil counts, respectively. Conversely, the highest dose of BQ-123 decreased Hb, total cell and neutrophil counts and MPO levels by 36, 35, 42 and 70%, respectively. These results support a role for ET in AR lung injuries. They also suggests that blocking ETA-R may be beneficial, while blockade of ETB-R (using a high dose of SE 209670) may be detrimental. A beneficial ETB-mediated response may exist that naturally interferes with events triggered by the formation of immune complexes such as cell accumulation and their subsequent activation leading to acute lung injury. (C) 1998 Academic Press.