Paraquat-induced pulmonary fibrosis. Role of the alveolitis in modulating the development of fibrosis

Abstract

Paraquat, a widely used herbicide, can cause severe and often fatal pulmonary fibrosis in humans and in laboratory animals. Although paraquat is known to be directly cytotoxic to lung parenchymal cells, the mechanism by which this leads to pulmonary fibrosis is not completely understood. In a model of paraquat-induced pulmonary fibrosis using the cynomolgus monkey, the administration of paraquat (10 mg/kg/wk subcutaneously for 2 consecutive wk) was followed by an alveolitis comprised of neutrophils and macrophages in the exposed animals as evaluated by lung morphologic examination and bronchoalveolar lavage. The lungs of the exposed animals showed typical interstitial fibrosis within 4 to 8 wk. At 1 to 2 wk after paraquat exposure, bronchoalveolar lavage cells harvested from the paraquat-exposed animals were spontaneously releasing a chemotactic factor for neutrophils, thus providing a possible mechanism for the recruitment of neutrophils to the alveolar structures. Lavage fluid from paraquat-exposed animals contained increased amounts of the fibroblast chemoattractant fibronectin (paraquat, 3.1 +/- 0.3 ng/micrograms albumin; control, 1.6 +/- 0.7 ng/micrograms albumin; p less than 0.05), and alveolar macrophages from these animals showed increased fibronectin production suggesting that local production accounted for part of the increased amounts of this glycoprotein (paraquat, 6.1 +/- 2.5 ng/10(6) cell/h; control, 1.4 +/- 0.5 ng/10(6) cell/h; p less than 0.05). In addition, alveolar macrophages from the exposed animals were spontaneously releasing a growth factor for fibroblasts, and normal alveolar macrophages exposed to paraquat in vitro were induced to release this growth factor.(ABSTRACT TRUNCATED AT 250 WORDS)