Histological Examination of the Relationship between Respiratory Disorders and Repetitive Microaspiration Using a Rat Gastro-Duodenal Contents Reflux Model

Abstract

Microaspiration due to gastroesophageal reflux (GER) has been suggested as a factor contributing to the development and exacerbation of several respiratory disorders. To explore the relationship between GER and respiratory disorders, we histologically examined the bilateral lungs of a rat gastroduodenal contents reflux model, which was previously used to investigate the histogenesis of Barrett's esophagus and esophageal carcinoma. GER was surgically induced in male Wistar rats. The bilateral lungs of the reflux rats were examined with hematoxylin and eosin (HE), PAS-Alcian blue, and Azan staining at 10 and 20 weeks after surgery. Immunohistochemical staining of CD68 and α-SMA was also performed. Aspiration pneumonia with severe peribronchiolar neutrophilic and lymphocytic infiltrates, goblet cell hyperplasia, prominence of blood vessels, and increased thickness of the smooth muscle layer were detected. Bronchiolitis obliterans (BO)-like lesions comprising granulation tissue with macrophages, spindle cells, and multinucleated giant cells in the lumen of respiratory bronchioles were observed in the bilateral lungs of the reflux animals. These findings suggest that the severe inflammation and the BO-like lesions may play a role in exacerbation of the forced expiratory volume in 1 second (FEV 1) in human cases. In conclusion, we speculate that repetitive microaspiration due to GER may contribute to the exacerbation of various respiratory diseases, particularly asthma and chronic obstructive pulmonary disease (COPD), and the development of BO syndrome following lung transplantation. The reflux model is a good tool for examining the causal relationships between GER and respiratory disorders.

The Efficacy of the Upright Position on Gastro-Esophageal Reflux and Reflux-Related Respiratory Symptoms in Infants With Chronic Respiratory Symptoms

“…There are two possible mechanisms to explain the relationship between GER and reflux-related respiratory symptoms: a direct inflammatory effect through microaspiration,31 or an indirect effect through esophageal distension and vagal stimulation 13,32. Rosen et al13 reported that proximal reflux is strongly associated with respiratory symptoms (OR, 1.31; 95% CI, 1.01-1.69) and that 75% of non-acid reflux, compared with 8.8% of acid reflux, reaches the proximal esophagus in children with persistent respiratory symptoms and who take antacid medications.…”

Chronic aspiration shifts the immune response from adaptive immunity to innate immunity in a murine model of asthma

“…Thus, although studies using our model of aspiration under anesthesia preclude more frequent aspiration, it seems likely that such studies may be very worthwhile. One possible means by which this may be accomplished is the induction of aspiration using a surgical approach [38]. However, such models cannot distinguish between the effect of actual aspiration and the effects of vagally-mediated reflex bronchospasm, which does not require aspiration.…”

Changes in the pattern of fibrosis in the rat lung with repetitive orotracheal instillations of gastric contents: evidence of persistent collagen accumulation

“…Appel et al (1) described the characteristics of the inflammatory response to chronic localized aspiration in rats whereas other investigators studied inflammation and fibrosis as outcomes at the end of protocols involving repetitive tracheal instillations of specific components of gastroduodenal contents (6,27). In addition, a surgical gastroduodenal contents reflux model has been developed to study airway effects (22). However, little is known about the time course of ECM changes during repair following chronic aspiration of gastric contents as those that have been described in other models of lung injury that evolve to fibrosis (30,35).…”