title: The spontaneously hypertensive rat: an experimental model of sulfur dioxide-induced airways disease.
abstract: Chronic obstructive pulmonary disease (COPD) is characterized by airway obstruction, inflammation, and mucus hypersecretion, features that are common in bronchitis, emphysema, and often asthma. However, current rodent models do not reflect this human disease. Because genetically predisposed spontaneously hypertensive (SH) rats display phenotypes such as systemic inflammation, hypercoagulation, oxidative stress, and suppressed immune function that are also apparent in COPD patients, we hypothesized that SH rat may offer a better model of experimental bronchitis. We, therefore, exposed SH and commonly used Sprague Dawley (SD) rats (male, 13- to 15-weeks old) to 0, 250, or 350 ppm sulfur dioxide (SO(2)), 5 h/day for 4 consecutive days to induce airway injury. SO(2) caused dose-dependent changes in breathing parameters in both strains with SH rats being slightly more affected than SD rats. Increases in bronchoalveolar lavage fluid (BALF) total cells and neutrophilic inflammation were dose dependent and significantly greater in SH than in SD rats. The recovery was incomplete at 4 days following SO(2) exposure in SH rats. Pulmonary protein leakage was modest in either strain, but lactate dehydrogenase and N-acetyl glucosaminidase activity were increased in BALF of SH rats. Airway pathology and morphometric evaluation of mucin demonstrated significantly greater impact of SO(2) in SH than in SD rats. Baseline differences in lung gene expression pattern suggested marked immune dysregulation, oxidative stress, impairment of cell signaling, and fatty acid metabolism in SH rats. SO(2) effects on these genes were more pronounced in SH than in SD rats. Thus, SO(2) exposure in SH rats may yield a relevant experimental model of bronchitis.
authors.affiliation: Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, 27711, USA. kodavanti.urmila@epa.gov
authors.forename: Urmila P
authors.initials: UP
authors.lastname: Kodavanti
authors.forename: Mette C
authors.initials: MC
authors.lastname: Schladweiler
authors.forename: Allen D
authors.initials: AD
authors.lastname: Ledbetter
authors.forename: Roselia Villalobos
authors.initials: RV
authors.lastname: Ortuno
authors.forename: Marie
authors.initials: M
authors.lastname: Suffia
authors.forename: Paul
authors.initials: P
authors.lastname: Evansky
authors.forename: Judy H
authors.initials: JH
authors.lastname: Richards
authors.forename: Richard H
authors.initials: RH
authors.lastname: Jaskot
authors.forename: Ronald
authors.initials: R
authors.lastname: Thomas
authors.forename: Edward
authors.initials: E
authors.lastname: Karoly
authors.forename: Yuh-Chin T
authors.initials: YC
authors.lastname: Huang
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Costa
authors.forename: Peter S
authors.initials: PS
authors.lastname: Gilmour
authors.forename: Kent E
authors.initials: KE
authors.lastname: Pinkerton
mesh_terms: D000118:Acetylglucosaminidase / Q000378:metabolism; D000280:Administration, Inhalation; D000818:Animals; D001991:Bronchitis / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000235:genetics; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D009093:Mucus / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015656:Respiratory Mechanics / Q000187:drug effects; D013045:Species Specificity; D013458:Sulfur Dioxide / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015431:Weight Loss / Q000187:drug effects
chemical_list: D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C513296:Cxcl2 protein, rat; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D013458:Sulfur Dioxide; D007770:L-Lactate Dehydrogenase; D000118:Acetylglucosaminidase