Haptoglobin (Hp), a member of the acute-phase reactants, has long been known as a major hemoglobin-binding protein associated with hemoglobin catabolism. Recent studies indicate that another important biologic function of Hp is the modulation of the immune response. We found that Hp is expressed at high levels in specific cells, including alveolar macrophages and eosinophils in diseased or inflamed human lung tissues, but not in the normal lung. Expression of the human Hp gene was studied in two transgenic mouse lines carrying a 9-kb human Hp 2 gene. In both lines, the human Hp transgene was expressed constitutively in alveolar macrophages at a high level, whereas the endogenous mouse Hp was synthesized in airway epithelial cells. Expression of the human Hp transgene in lung cells was upregulated when the transgenic mice were treated with endotoxin. In humans and in Hp transgenic mice, human Hp messenger RNA was also detected in circulating eosinophils, but not in other blood cells. Our findings suggest that Hp is involved in a variety of lung inflammatory diseases, including respiratory allergy and asthma. The transgenic mouse line that overexpresses the human Hp gene in alveolar macrophages and eosinophils is a promising system for investigating the function of Hp in vivo during lung inflammation.