Common and distinct mechanisms of induced pulmonary fibrosis by particulate and soluble chemical fibrogenic agents.
Pulmonary fibrosis results from the excessive deposition of collagen fibers and scarring in the lungs with or without an identifiable cause. The mechanism(s) underlying lung fibrosis development is poorly understood, and effective treatment is lacking. Here we compared mouse lung fibrosis induced by pulmonary exposure to prototypical particulate (crystalline silica) or soluble chemical (bleomycin or paraquat) fibrogenic agents to identify the underlying mechanisms. Young male C57BL/6J mice were given silica (2 mg), bleomycin (0.07 mg), or paraquat (0.02 mg) by pharyngeal aspiration. All treatments induced significant inflammatory infiltration and collagen deposition, manifesting fibrotic foci in silica-exposed lungs or diffuse fibrosis in bleomycin or paraquat-exposed lungs on day 7 post-exposure, at which time the lesions reached their peaks and represented a junction of transition from an acute response to chronic fibrosis. Lung genome-wide gene expression was analyzed, and differential gene expression was confirmed by quantitative RT-PCR, immunohistochemistry, and immunoblotting for representative genes to demonstrate their induced expression and localization in fibrotic lungs. Canonical signaling pathways, gene ontology, and upstream transcription networks modified by each agent were identified. In particular, these inducers elicited marked proliferative responses; at the same time, silica preferentially activated innate immune functions and the defense against foreign bodies, whereas bleomycin and paraquat boosted responses related to cell adhesion, platelet activation, extracellular matrix remodeling, and wound healing. This study identified, for the first time, the shared and unique genes, signaling pathways, and biological functions regulated by particulate and soluble chemical fibrogenic agents during lung fibrosis, providing insights into the mechanisms underlying human lung fibrotic diseases.
Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Mailstop 3014, 1095 Willowdale Road, Morgantown, WV, 26505, USA.
Jie
J
Dong
Department of Biostatistics, Yale University School of Public Health, New Haven, CT, 06520, USA.
Xiaoqing
X
Yu
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV, 26505, USA.
Dale W
DW
Porter
Pathology and Physiology Research Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV, 26505, USA.
Lori A
LA
Battelli
Biostatistics and Epidemiology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, WV, 26505, USA.
Michael L
ML
Kashon
Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Mailstop 3014, 1095 Willowdale Road, Morgantown, WV, 26505, USA. qam1@cdc.gov.
Qiang
Q
Ma
D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects*; D016678:Genome; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D010269:Paraquat / Q000633:toxicity*; D052638:Particulate Matter / Q000633:toxicity; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000633:toxicity; D012995:Solubility; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D052638:Particulate Matter; D014157:Transcription Factors; D001761:Bleomycin; D012822:Silicon Dioxide; D010269:Paraquat
Bleomycin; Genome-wide gene expression; Inflammation; Paraquat; Pulmonary fibrosis; Silica