Characterization of the innate immune response to chronic aspiration in a novel rodent model

Appel, James Z.; Lee, Sean M.; Hartwig, Matthew G.; Li, Bin; Hsieh, Chong Chao; Cantu, Edward; Yoon, Yonghan; Lin, Song; Parker, William; Davis, Robert D.

doi:10.1186/1465-9921-8-87

Cited by 91 publications

(64 citation statements)

References 40 publications

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“…It has been hypothesized that chronic microaspiration (i.e., tracheobronchial aspiration of small amounts of gastric secretions) due to gastroesophageal reflux (GER) may cause repetitive subclinical injury to the lung leading to pulmonary fibrosis (3,4). Evidence from experimental models in animals and descriptive studies in humans supports this concept (3,(5)(6)(7)(8)(9).…”

mentioning

confidence: 61%

Gastroesophageal Reflux Therapy Is Associated with Longer Survival in Patients with Idiopathic Pulmonary Fibrosis

Lee¹,

Ryu

Elicker³

et al. 2011

Am J Respir Crit Care Med

392

283

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Rationale: Gastroesophageal reflux (GER) is highly prevalent in patients with idiopathic pulmonary fibrosis (IPF). Chronic microaspiration secondary to GER may play a role in the pathogenesis and natural history of IPF. Objectives: To investigate the relationship between GER-related variables and survival time in patients with IPF. Methods: Regression analysis was used to investigate the relationship between GER-related variables and survival time in a retrospectively identified cohort of patients with well-characterized IPF from two academic medical centers. Measurements and Main Results: Two hundred four patients were identified for inclusion. GER-related variables were common in this cohort: reported symptoms of GER (34%), a history of GER disease (45%), reported use of GER medications (47%), and Nissen fundoplication (5%). These GER-related variables were significantly associated with longer survival time on unadjusted analysis. After adjustment, the use of GER medications was an independent predictor of longer survival time. In addition, the use of gastroesophageal reflux medications was associated with a lower radiologic fibrosis score. These findings were present regardless of center. Conclusions: The reported use of GER medications is associated with decreased radiologic fibrosis and is an independent predictor of longer survival time in patients with IPF. These findings further support the hypothesis that GER and chronic microaspiration may play important roles in the pathobiology of IPF.

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mentioning

confidence: 61%

Gastroesophageal Reflux Therapy Is Associated with Longer Survival in Patients with Idiopathic Pulmonary Fibrosis

Lee¹,

Ryu

Elicker³

et al. 2011

Am J Respir Crit Care Med

392

283

View full text Add to dashboard Cite

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“…Moreover, BA aspiration has also been linked with airway inflammation, whereby a correlation between alveolar neutrophils (8) and interleukin-8 (IL-8) (11,14) with BAL fluid BAs has been found. Moreover, in a rodent model of chronic aspiration, BA aspiration has also been associated with increased BAL fluid tumor necrosis factor alpha (TNF-␣) (17).…”

mentioning

confidence: 99%

Bile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response

et al. 2014

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bGastroesophageal reflux (GER) frequently occurs in patients with respiratory disease and is particularly prevalent in patients with cystic fibrosis. GER is a condition in which the duodenogastric contents of the stomach leak into the esophagus, in many cases resulting in aspiration into the respiratory tract. As such, the presence of GER-derived bile acids (BAs) has been confirmed in the bronchoalveolar lavage fluid and sputum of affected patients. We have recently shown that bile causes cystic fibrosis-associated bacterial pathogens to adopt a chronic lifestyle and may constitute a major host trigger underlying respiratory infection. The current study shows that BAs elicit a specific response in humans in which they repress hypoxia-inducible factor 1␣ (HIF-1␣) protein, an emerging master regulator in response to infection and inflammation. HIF-1␣ repression was shown to occur through the 26S proteasome machinery via the prolyl hydroxylase domain (PHD) pathway. Further analysis of the downstream inflammatory response showed that HIF-1␣ repression by BAs can significantly modulate the immune response of airway epithelial cells, correlating with a decrease in interleukin-8 (IL-8) production, while IL-6 production was strongly increased. Importantly, the effects of BAs on cytokine production can also be more dominant than the bacterium-mediated effects. However, the effect of BAs on cytokine levels cannot be fully explained by their ability to repress HIF-1␣, which is not surprising, given the complexity of the immune regulatory network. The suppression of HIF-1 signaling by bile acids may have a significant influence on the progression and outcome of respiratory disease, and the molecular mechanism underpinning this response warrants further investigation.

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“…In addition to the well reported clinical association between GER in SSc and lung involvement (18)(19)(20), data from animal models and in vitro analysis have provided a biologic rationale supporting the role of microaspiration in the genesis and/or progression of ILD. Pepsin and bile acids have a citotoxic effect on epithelial cells and can induce a pro-inflammatory response including expression of cytokines and chemokines (21)(22)(23). In a rat model of chronic aspiration, interstitial pneumonitis changes followed the instillation into the airways of either whole gastric or neutralized gastric fluid, but not of hydrochloric acid (24).…”

Section: The Role Of Pepsinmentioning

confidence: 99%

The role of gastro-esophageal reflux (GER) in systemic sclerosis and lung fibrosis

Lauretis¹

2014

SOB

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SummarySystemic sclerosis (SSc) is an autoimmune condition characterized by tissue fibrosis of the skin and internal organs. A significant subgroup of SSc patients develops progressive interstitial lung disease (ILD) leading to pulmonary fibrosis similar to IPF (idiopathic pulmonary fibrosis). Gastro-esophageal reflux (GER) has been suggested as a driving factor in the pathogenesis of both SSc-ILD and IPF. The esophagus is affected in 50-82% of patients with SSc. Gastric reflux may be liquid, gaseous, or particulate; acid or nonacid; distal (localized to the distal oesophagus) or proximal (reaching the proximal oesophagus and pharynx). Reflux to the proximal oesophagus, which is intuitively linked to microaspiration into the lungs, appears to be quite common in patients with ILD-SSc and IPF. Importantly, a significant proportion of GER reflux is asymptomatic. Concentration of pepsin and bile acids in bronchoalveolar lavage (BAL) and exhaled breath condensate (EBC) have been investigated as biomarkers of microaspiration in various respiratory diseases. The confirmation of a causative link of microaspiration in the genesis and progression of lung fibrosis would have a major impact in the management of ILD-SSc patients. It is likely that proteases such as pepsin, and not the acidity, are the primary target for future therapies. Potent inhibitors specific for proteases, e.g. pepstatin, are available and have been tested in phase-III clinical trials.

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Characterization of the innate immune response to chronic aspiration in a novel rodent model

Cited by 91 publications

References 40 publications

Gastroesophageal Reflux Therapy Is Associated with Longer Survival in Patients with Idiopathic Pulmonary Fibrosis

Gastroesophageal Reflux Therapy Is Associated with Longer Survival in Patients with Idiopathic Pulmonary Fibrosis

Bile Acids Repress Hypoxia-Inducible Factor 1 Signaling and Modulate the Airway Immune Response

The role of gastro-esophageal reflux (GER) in systemic sclerosis and lung fibrosis

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