Elastase- and LPS-exposed mice display altered responses to rhinovirus infection.
Viral infection is associated with approximately one-half of acute exacerbations of chronic obstructive pulmonary disease (COPD), which in turn, accelerate disease progression. In this study, we infected mice exposed to a combination of elastase and LPS, a constituent of cigarette smoke and a risk factor for development of COPD, with rhinovirus serotype 1B, and examined animals for viral persistence, airway resistance, lung volume, and cytokine responses. Mice exposed to elastase and LPS once a week for 4 wk showed features of COPD such as airway inflammation and obstruction, goblet cell metaplasia, reduced lung elastance, increased total lung volume, and increased alveolar chord length. In general, mice exposed to elastase or LPS alone showed intermediate effects. Compared with rhinovirus (RV)-infected PBS-exposed mice, RV-infected elastase/LPS-exposed mice showed persistence of viral RNA, airway hyperresponsiveness, increased lung volume, and sustained increases in expression of TNFalpha, IL-5, IL-13, and muc5AC (up to 14 days postinfection). Furthermore, virus-induced IFNs, interferon response factor-7, and IL-10 were deficient in elastase/LPS-treated mice. Mice exposed to LPS or elastase alone cleared virus similar to PBS-treated control mice. We conclude that limited exposure of mice to elastase/LPS produces a COPD-like condition including increased persistence of RV, likely due to skewing of the immune response towards a Th2 phenotype. Similar mechanisms may be operative in COPD.
Sajjan
Umadevi
U
Department of Pediatrics and Communicable Diseases, University of Michigan, 1150 W. Medical Center Dr., Rm. 3570, MSRBII, Box 5688, Ann Arbor, MI 48109-5688, USA.
Ganesan
Shyamala
S
Comstock
Adam T
AT
Shim
Jee
J
Wang
Qiong
Q
Nagarkar
Deepti R
DR
Zhao
Ying
Y
Goldsmith
Adam M
AM
Sonstein
Joanne
J
Linn
Marisa J
MJ
Curtis
Jeffrey L
JL
Hershenson
Marc B
MB
D000818:Animals; D005260:Female; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology; D019570:Inhalation Exposure; D007372:Interferons / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D055271:Mucin 5AC / Q000235:genetics / Q000378:metabolism; D009929:Organ Size / Q000187:drug effects; D010196:Pancreatic Elastase / Q000008:administration & dosage* / Q000494:pharmacology; D010850:Picornaviridae Infections / Q000150:complications / Q000276:immunology* / Q000503:physiopathology / Q000821:virology*; D011014:Pneumonia / Q000150:complications / Q000473:pathology / Q000503:physiopathology / Q000821:virology; D012129:Respiratory Function Tests; D012229:Rhinovirus / Q000502:physiology*; D034421:Sus scrofa; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D018793:Interleukin-13; D008070:Lipopolysaccharides; C524679:Muc5ac protein, mouse; D055271:Mucin 5AC; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007372:Interferons; D010196:Pancreatic Elastase