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

C. I. Schoenberger, S. I. Rennard, P. B. Bitterman

Research output: Contribution to journalArticle

70 Scopus citations

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 cynomolgous 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/μg albumin; control, 1.6 ± 0.7 ng/μg albumin; p < 0.05), and alveolar macrophages from these animals showed increased fibronectin production suggesting that local prduction accounted for part of the increased amounts of this glycoprotein (paraquat, 6.1 ± 2.5 ng/106 cell/h; control, 1.4 ± 0.5 ng/106 cell/h; p < 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. These data suggest: (1) that paraquat induces an alveolitis comprised of neutrophils and macrophages that precedes the development of pulmonary fibrosis; (2) that alveolar macrophages may play a role in the recruitment of neutrophils by releasing a chemotactic factor for neutrophils; (3) that alveolar macrophages release both fibronectin and a growth factor for fibroblasts after paraquat exposure, thus providing a mechanism whereby fibroblasts may be recruited to the alveolar structures and then stimulated to replicate. Thus, in addition to its known cytotoxic properties for lung parenchymal cells, paraquat exposure induces an alveolitis characterized by activated macrophages and neutrophils, cells that have effector processes that modulate, at least in part, some of the lung parenchymal damage and fibrosis associated with this herbicide.

Original languageEnglish (US)
Pages (from-to)168-173
Number of pages6
JournalAmerican Review of Respiratory Disease
Volume129
Issue number1
StatePublished - 1984
Externally publishedYes

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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