Characterization of the innate immune response to chronic aspiration in a novel rodent model.
BACKGROUND
Although chronic aspiration has been associated with several pulmonary diseases, the inflammatory response has not been characterized. A novel rodent model of chronic aspiration was therefore developed in order to investigate the resulting innate immune response in the lung.


METHODS
Gastric fluid or normal saline was instilled into the left lung of rats (n = 48) weekly for 4, 8, 12, or 16 weeks (n = 6 each group). Thereafter, bronchoalveolar lavage specimens were collected and cellular phenotypes and cytokine concentrations of IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma, TNF-alpha, and TGF-beta were determined.


RESULTS
Following the administration of gastric fluid but not normal saline, histologic specimens exhibited prominent evidence of giant cells, fibrosis, lymphocytic bronchiolitis, and obliterative bronchiolitis. Bronchoalveolar lavage specimens from the left (treated) lungs exhibited consistently higher macrophages and T cells with an increased CD4:CD8 T cell ratio after treatment with gastric fluid compared to normal saline. The concentrations of IL-1alpha, IL-1beta, IL-2, TNF-alpha and TGF-beta were increased in bronchoalveolar lavage specimens following gastric fluid aspiration compared to normal saline.


CONCLUSIONS
This represents the first description of the pulmonary inflammatory response that results from chronic aspiration. Repetitive aspiration events can initiate an inflammatory response consisting of macrophages and T cells that is associated with increased TGF-beta, TNF-alpha, IL-1alpha, IL-1beta, IL-2 and fibrosis in the lung. Combined with the observation of gastric fluid-induced lymphocyitic bronchiolitis and obliterative bronchiolitis, these findings further support an association between chronic aspiration and pulmonary diseases, such as obliterative bronchiolitis, pulmonary fibrosis, and asthma.
Transplant Immunobiology Laboratory, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. appel003@mc.duke.edu
James Z
JZ
Appel
Sean M
SM
Lee
Matthew G
MG
Hartwig
Bin
B
Li
Chong-Chao
CC
Hsieh
Edward
E
Cantu
Yonghan
Y
Yoon
Shu S
SS
Lin
William
W
Parker
R Duane
RD
Davis
D000818:Animals; D001988:Bronchiolitis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005744:Gastric Acid; D005764:Gastroesophageal Reflux / Q000150:complications; D007113:Immunity, Innate / Q000276:immunology*; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000473:pathology; D008297:Male; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D053120:Respiratory Aspiration / Q000150:complications*
D016207:Cytokines