Introduction

Many co-morbidities have been identi ed in patients with idiopathic pulmonary brosis (IPF) and there is growing interest in their impact on disease pathogenesis and outcomes. The importance of the relationship between the upper GI tract and the respiratory system has been long appreciated. In as early as 1927 Vinson reported the development of a pulmonary abscess in a patient with achalasia [1]. Bartlett and Gorbach described the “triple threat” of aspiration syndromes according to the inhaled substance which they categorized as toxic fuids (including gastric acid), bacterial pathogens, and inert substances (fuids or particulates) [2]. Later, in 1976 Mays et al. rst described the presence of gastric secretions in the tracheobronchial aspirates of patients with pulmonary brosis and suggested a possible causative link [3].

Under normal conditions gastric contents are prevented from entering the esophagus by a number of mechanisms at the level of the gastroesophageal junction (GEJ). The lower esophageal sphincter is a segment of continuously contracted smooth muscle that is primarily responsible for maintaining the integrity of the GEJ in addition to the diaphragmatic hiatus and the gastric cardia. The neurologic control of this region is complex to facilitate appropriate anterograde fow of food while preventing refux of gastric contents. With disruption of any of these mechanisms refux can occur and ultimately enter the lower respiratory tract [4].

C. Scallan · G. Raghu (*)

Department of Medicine, Center for Interstitial Lung Disease, UW Medical Center, University of Washington, Seattle, WA, USA e-mail: ciaran.scallan@medportal.ca; graghu@uw.edu

Several different terms for the description of these processes exist in the literature. For clarity, we will de ne the terms used in this chapter below.

Gastroesophageal Refux (GER) is de ned as the refux of gastric contents into the esophagus. These contents can be either acidic (esophageal pH < 4.0) or non-acidic (esophageal pH > 7.0) and can occur with or without symptoms.

Gastroesophageal Refux Disease (GERD) is a condition that develops when the refux of gastric contents causes symptoms, macroscopic changes with or without microscopic features at the level of the GE junction, and complications [5]. These have been divided into esophageal and extraesophageal syndromes.

Microaspiration is the entry of small particles of oropharyngeal or gastric contents into the lower respiratory tract. It is subclinical and separate from the other conditions associated with aspiration (i.e., aspiration pneumonitis or aspiration pneumonia). This could be silent or overt; it is often silent and hence called “silent aspiration.” Microaspiration is the common pathway by which the lung is affected and there are several proposed mechanisms contributing to the pathogenesis of IPF which will be explored later in this chapter.

Epidemiology/Anatomy and Physiology/

Pathobiology

Epidemiology

Multiple co-morbidities are often present in patients with IPF and there has been a high reported prevalence of GER and GERD. Estimates vary widely (0–94%) which is largely due to the signi cant variation in how patients are evaluated and the presence or absence of GER speci c symptoms [6– 9]. When rigorous and systematic testing is used to evaluate for the presence of acid refux in patients with IPF it is clear that there is an extremely high prevalence [9]. Hiatal hernia

has been shown to have a high prevalence in IPF patients (up to 53%) and its presence has been associated with increased respiratory associated mortality [3, 10].

Anatomy/Embryogenesis of the Upper GI

and Respiratory Tracts

The respiratory and upper gastrointestinal systems are closely linked beginning in the stages of early human development (Fig. 23.1). During gastrulation the three germ layers are formed and as the endoderm is folded into a tube the foregut is established. On day 22 the respiratory diverticulum arises from the ventral portion of the foregut and eventually develops into the lower respiratory system. A layer of mesoderm surrounds the developing trachea preventing the development of peripheral airway structures and the tracheoesophageal ridges separate it from the developing esophagus. The dorsal portion of the foregut tube develops into the esophagus and the most caudal portion develops into the pharyngeal clefts and eventual pharynx [11].

The close relationship between these two systems persists into adult life given the proximity of the openings of larynx and proximal esophagus. The transit of esophageal and gastric contents into the respiratory tract allows them to infuence the biology of the respiratory epithelium and alveoli.

Fig. 23.1  Outpouching of foregut endoderm and respiratory tract tissues during human embryogenesis. The respiratory diverticula that form the pulmonary system and the stomach are in green

Gastric Contents

The stomach secretes approximately 2 L of gastric fuid per day and has several constituents: water, hydrochloric acid (HCl), mucous, intrinsic factor, growth, and immune factors. Other components found in gastric fuid include bile acids and salts, food particles, and endotoxins from bacteria lysed in the stomach. HCl is produced by parietal cells and functions to decrease the pH of gastric fuid, kill pathogens in the stomach, and activate pepsin from pepsinogen.

Several mechanisms exist to protect the gastric mucosa from both the low pH environment created by the secretion of HCl and the proteolytic action of pepsin. These include the secretion of protective mucous and bicarbonate by surface epithelial cells. The lung epithelium lacks these protective mechanisms and while playing an integral role in the digestion of food and destruction of pathogenic bacteria the refux and microaspiration of gastric contents has several deleterious effects in the respiratory system.

Pathobiology of GER/Microaspirate in the Lungs of Patients with IPF

The entry of gastric contents into the respiratory system has long been understood to have negative consequences (Fig. 23.2). Mendelson rst described the clinical phenomenon of aspiration pneumonia in obstetrical anesthesia cases in 1941 [12]. There have been several studies in both animal models and humans that support the model of microaspiration as a contributor to the development of pulmonary brosis. In animal models, instillation of acid solutions into the lung promote increased cell membrane permeability, an infammatory and immune response, and increased broblast proliferation leading to brosis [13–15]. Other components of gastric juice have also been postulated to contribute to progressive brosis. Perng et al. cultured primary human alveolar epithelial cells and exposed them to chenodeoxycholic acid (CD) a component of human biliary secretions. CD exposure was associated with increased expression and release of TGF-beta in addition to increased activity of co-­ cultured broblasts [16]. Pepsin, another major component of gastric juice, has been identi ed in the bronchoalveolar lavage (BAL) samples of IPF patients with acute exacerbations [17]. Several models have identi ed pepsin as a potent regulator of epithelial cell biology by affecting cytokine secretion, infammation, and cell turnover [18, 19].

Sleep is a particularly vulnerable time for the respiratory system with regard to exposure to refux and microaspiration. Several physiologic changes occur with sleep including a decrease in upper esophageal pressure [20]. In normal subjects, Gleeson et al. identi ed that nearly half had objective evidence of aspiration after a night’s sleep [21]. Obstructive