Gene expression profiles reveal increased mClca3 (Gob5) expression and mucin production in a murine model of asbestos-induced fibrogenesis.
To elucidate genes important in development or repair of asbestos-induced lung diseases, gene expression was examined in mice after inhalation of chrysotile asbestos for 3, 9, and 40 days. We identified changes in the expression of genes linked to proliferation (cyclin B2, CDC20, and CDC28 protein kinase regulatory subunit 2), inflammation (CCL9, CCL6, complement component 1, chitinase3-like 3, TNF superfamily member 10, and IL-1B), and matrix remodeling (MMP12, MMP3, integrin alphaX, and cathepsins K, Z, B, and S). The most highly induced gene at all time points was mclca3 (gob5), a putative calcium-activated chloride channel involved in the regulation of mucus production and/or secretion. Using histochemistry, we demonstrated accumulation of mucus and increased mClca3 protein in the bronchiolar epithelium of asbestos-exposed mice at all time points but peaking at 9 days. Cytokine levels (interleukin-1beta, interleukin-4, interleukin-6) in bronchoalveolar lavage fluid also increased at 9 days, suggesting Th2-mediated immunity may play a role in asbestos-induced mucus production. In contrast, levels of cathepsin K, a potent elastase, increased between 3 and 40 days at both the mRNA and protein levels, localizing primarily in CD45-positive leukocytes and interstitial cells. Identification of genes involved in lung injury and remodeling after asbestos exposure could aid in defining mechanisms of airborne particulate-induced disease and in developing therapeutic strategies.
Sabo-Attwood
Tara
T
Department of Pathology, University of Vermont, 89 Beaumont Ave., HSRF 218, Burlington, VT 05405, and the Pediatric Pulmonary Division, Children's Hospital of Pittsburgh, PA, USA.
Ramos-Nino
Maria
M
Bond
Jeffrey
J
Butnor
Kelly J
KJ
Heintz
Nicholas
N
Gruber
Achim D
AD
Steele
Chad
C
Taatjes
Douglas J
DJ
Vacek
Pamela
P
Mossman
Brooke T
BT
D000818:Animals; D001194:Asbestos / Q000633:toxicity; D001195:Asbestosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D018118:Chloride Channels / Q000235:genetics*; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D015870:Gene Expression; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009077:Mucins / Q000096:biosynthesis*; D009088:Mucoproteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010196:Pancreatic Elastase / Q000096:biosynthesis; D011658:Pulmonary Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D020545:Respiratory Mucosa / Q000503:physiopathology
D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D016207:Cytokines; D009077:Mucins; D009088:Mucoproteins; D012333:RNA, Messenger; D001194:Asbestos; D010196:Pancreatic Elastase