Roles of Endothelins and their Receptors in Immune Complex-Induced/Polymorphonuclear-Mediated Lung Injury (Reversed Passive Arthus Reaction) in CD-1 Mice

Abstract 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 ET A (BQ-123) or a non-selective ET A /ET B -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 SB 209670 reduced Hb levels by 21% ( P A -R may be beneficial, while blockade of ET B -R (using a high dose of SB 209670) may be detrimental. A beneficial ET B -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.