Figure 4: Macrophage infiltration following chronic aspiration of gastric fluid. The relative macrophage quantities in bronchoalveolar lavage (BAL) specimens following chronic aspiration of either gastric fluid or normal saline are shown. The ratio of macrophages in the left to the macrophage in the right lung is shown as a function of time. In the inset, the ratio of macrophages in the left to the macrophages in the right lung is shown for all rats, regardless of the duration of treatment. †p < 0.10, *p < 0.05, **p < 0.01 based on two-tailed Student's t test.

Mentions: Based on FACS analysis, the numbers of macrophages were increased in BAL specimens from left (treated) lungs of rats receiving gastric fluid, but not in BAL specimens from right (untreated) lungs of rats receiving gastric fluid, left lungs from rats receiving normal saline, or left lungs from untreated rats. Furthermore, the ratio of macrophages in the left (treated) lung to macrophages in the right (untreated) lung was significantly higher among rats receiving gastric fluid for 4 weeks compared to rats receiving normal saline for the same time period (p = 0.04). This trend was still observed after 8, 12, and 16 weeks, although the difference between experimental animals and controls was not significant (Figure 4). Among all rats receiving gastric fluid, the ratio of macrophages in the left (treated) lung to macrophages in the right (untreated) lung was significantly higher among rats receiving gastric fluid compared to rats receiving normal saline (Figure 4 inset, p < 0.01).

Appel JZ, Lee SM, Hartwig MG, Li B, Hsieh CC, Cantu E, Yoon Y, Lin SS, Parker W, Davis RD - Respir. Res. (2007)

Bottom Line: 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.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.

Affiliation: Transplant Immunobiology Laboratory, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA. appel003@mc.duke.edu

Abstract: 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.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.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.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.