Idiopathic pulmonary fibrosis (IPF) is a terminal lung disease of largely unknown cause that cannot be adequately treated to this day. IPF has devastating symptoms and a survival prognosis of just around 2–3 years after diagnosis . Moreover, the quality of life of IPF patients is very poor, as the disease progresses rapidly. As the highest prevalence of IPF is in the sixth decade of life, the theory has been proposed that aging and its related biological processes participate in the progression of the disease . More recently, a substantial amount of evidence was found for the increased formation of reactive oxygen species (ROS) in IPF [3▪]. It has been suggested that injury to the lung epithelium could potentially be worsened by external triggers. One of the most commonly observed IPF triggers is cigarette smoking . Other triggering factors include exposure to manmade fibers (i.e., asbestos and glass wool fibers) [5,6], chronic infection , and air pollution [8▪]. Another piece of the IPF puzzle has come from studies revealing gastroesophageal reflux disease (GERD) as a possible alternative trigger for the development of IPF. This was first suggested a few decades ago when an increased prevalence of GERD was reported in patients diagnosed with IPF . More recently, the gastric acid components pepsin and bile salts were found in the bronchoalveolar lavage fluid of IPF patients . Remarkably, the direction of the association between GERD and IPF has not yet been established, as it is not clear whether IPF-related processes promote reflux, or whether microaspiration because of GERD causes IPF [8▪,10]. However, both IPF and GERD are characterized by increased oxidative stress and inflammation [11–13].
Currently prescribed pharmaceutical treatment for IPF mainly aims at reducing lung fibrosis-induced lung damage and thereby increases the survival rate . Additionally, proton pump inhibitors (PPIs) that are normally used to treat GERD have also been included in the IPF treatment regime, as previous case reports showed that it could reduce the progression of lung damage and increase survival rates . The use of antacids for treating IPF was also reported in a recent study, showing that approximately 75% of all the IPF patients involved in the study used antacids, whether or not combined with antifibrotic drugs [15▪▪]. Conversely, currently available studies indicate that earlier research regarding the addition of antisecretory medication was based on poor-quality evidence, whereas subsequent research did not show enough benefits to suggest improved survival. More importantly, they warned about worrisome adverse effects of PPIs, such as the increased risk of infection, decreased efficacy of pirfenidone, potential drug interactions, and nutrient deficiencies [1,16–18].
The rising global incidence rates of IPF  indicate that the current pharmaceutical approach is flawed and there is a pressing need for improved alternative or complementary treatment options. With the existing state of knowledge, it cannot be overlooked that ROS and inflammation play a role in the pathogenesis of both IPF and GERD. This raises the question whether antioxidant treatment could be a safer and more effective means to alleviate at least some of the symptoms of both conditions . Accordingly, the objective of this article is to review the currently available scientific literature regarding antioxidant supplementation as a possible treatment option for GERD-associated IPF.
INFLAMMATION AND OXIDATION MECHANISMS IN GASTROESOPHAGEAL REFLUX DISEASE
In the classical explanation of GERD, it was believed that mechanical disturbances in the lower esophageal sphincter and reflux of hydrochloric acid, pepsin, and bile salts directly damage the epithelial lining of the esophagus, which, as a complication, further develops into reflux esophagitis . However, the emergence of new evidence from both animal models and human studies suggested a novel view of GERD pathogenesis, describing it as a disease of inflammatory nature, resulting in increased production of cytokines, chemokines, and ROS, and in a disturbed endogenous antioxidant defense system . Table 1 highlights the main findings of the studies demonstrating changes in the inflammatory markers in GERD [9,12,22–31].
A tremendous contribution to the current understanding of GERD was made by an experiment on a rat model of GERD, based on the conventional view that acidic reflux in the esophagus would directly initiate damage to the epithelium. It found that direct damage to the epithelial cells was not present for a few weeks as was initially expected. In contrast to the classical explanation of GERD, the contents of the refluxate were found to damage the esophagus indirectly through induced secretion of proinflammatory cytokines that attracted lymphocytes, which eventually injured the epithelium . Similarly, in a clinical trial with sudden termination of PPI treatment in patients with severe esophagitis, inflammation was induced through T-lymphocytes, without injury or loss of surface cells . It appears that the endogenous preepithelial defense system is not strong enough to protect the esophagus from refluxate damage, explaining how inflammation can easily initiate damage to the unprotected epithelial cells of the esophagus .
In addition to inflammation, ROS also cause esophageal damage in GERD. In animals, refluxate alone was not enough to induce esophagitis. Various studies have provided evidence that damage to the mucous layer of the esophagus is caused by the presence of refluxate, which stimulates ROS formation, leading to oxidative stress, tissue damage, heartburn, and nausea and inhibition of the endogenous antioxidant system (see the summary of main findings in Table 1) [9,10,19–28,30]. The formation of ROS and inflammation play important roles in GERD pathogenesis, and often go hand in hand. This interplay was also demonstrated in a study with rats, where the inflammatory action of prostanoids, together with the formation of ROS, was involved in the development of GERD . In-vitro studies also found that refluxate did indeed induce ROS formation, which in turn mediated intracellular esophageal inflammation through hypoxia-inducible factors [13,34]. GERD patients were found to display hyperemia, which promoted infiltration by neutrophils and eosinophils in the mucosa of the esophagus, leading to disturbed ROS balance, inflammation, and cell necrosis [35▪]. Although these biochemical processes demonstrate the complexity of GERD, the emerging picture suggests the presence of a ‘vicious cycle’ of oxidative stress, ROS, and inflammation in GERD pathogenesis, which could potentially be a novel target for prospective therapeutic approaches. Without clearly realizing it, this idea might have been employed by those using histamine H2 blockers, which are known to be good antioxidants [36,37].
INFLAMMATION AND OXIDATION MECHANISMS IN IDIOPATHIC PULMONARY FIBROSIS
There is more and more evidence to suggest that harm to the lung tissue is mediated by ROS. As the diagnosis of IPF is most prevalent in the sixth decade of life , aging-related chronic pulmonary oxidative stress and reduced efficacy of the innate antioxidant defense system (glutathione) should not be ignored . Disturbed mitochondrial function is both age and IPF-related, suggesting that an increase in mitochondrial ROS production could cause fibrotic lung damage by transforming growth factor-β (TGF-β) signaling and NADPH oxidase 4 activation . ROS-mediated TGF-β1 production, in turn, promotes further proinflammatory, profibrotic damage to the lungs, as well as collagen accumulation [20,39]. Moreover, ROS enhance the progression of the disease via direct damage to DNA, proteins, and lung tissue by way of cellular membrane lipid oxidation, enzyme inactivation, changes in pro-inflammatory cytokine expression, and apoptosis. The link between ROS and inflammation was demonstrated in vivo, as increased cytokine IL-8 levels were not followed by higher IL-10 production, thus causing redox imbalance in the lungs of IPF patients . A particular feature of IPF is that oxidant damage is observed as a result of increased activation and expression of ROS-producing NOX enzymes and elevated mitochondrial oxygen superoxide and hydrogen peroxide production, because of dysfunctional mitochondria [3▪,41]. In addition, increased oxidative damage biomarkers were identified in IPF patients, such as 8-isoprostane, irreversibly oxidized proteins, 8-hydroxy-guanosine, and hydrogen peroxide in breath condensates [3▪].
Interestingly, IPF not only involves a rise in oxygen radical formation in the lungs but also a disturbed innate antioxidant defense system. One of the most potent cellular antioxidants, glutathione (GSH), was significantly decreased in IPF patients . Also, superoxide dismutase enzyme levels were reduced in the lung tissue of IPF patients and in murine model studies [43,44]. This further contributes to antioxidant imbalance and the progression of the disease. Hence, similar to GERD, ROS and inflammation play essential roles in the pathophysiology of IPF and might be relevant targets in the development of new therapeutic approaches.
ASSOCIATION BETWEEN GASTROESOPHAGEAL REFLUX DISEASE AND IDIOPATHIC PULMONARY FIBROSIS
In view of the increased prevalence of gastroesophageal reflux abnormalities in IPF patients , one possible direction in IPF treatment could involve addressing the GERD–IPF connection. Even though a clear relationship of causality has not been proven, several mechanisms have been suggested to be involved in connecting these two pathological conditions. The shared mechanisms behind this GERD–IPF connection are excellently discussed in a very recent review by Ghisa et al.[46▪]. It has been demonstrated that the presence of a weakened lower esophageal sphincter and hiatus hernia are risk factors for GERD, but are also common in IPF patients [47,48▪]. The prevalence of shared GERD and IPF symptoms is likely to be an attribute of aging, when the loss of gastric motility is common . A dysfunctional lower esophageal sphincter and hiatus hernia can then promote microaspiration and be the first symptom in the natural history of IPF [48▪]. The currently available evidence indicates that in IPF patients with GERD, reflux of gastric contents reaches the proximal part of the esophagus and then enters the lung by chronic microaspiration [50–52]. This hypothesis has been strengthened by the finding of reflux components in the samples of bronchoalveolar lavage fluid of IPF patients [1,8▪,53]. Chronic microaspiration of the refluxate is in turn assumed to initiate lung injury and induce abnormal wound healing, which may result in fibrosis and acute exacerbations [50,54]. Moreover, gastric refluxate has been associated with the promotion of inflammation in the lung epithelial cells through increased cytokine formation . Hence, scientific evidence shows that there is an association between IPF and GERD. To this day, however, ambiguity about the causal relationship of GERD and IPF still persists [8▪]. Clarification of the exact direction of this association might potentially contribute to better treatment options, improved quality of life, and consequently better prognoses, at least for the group of IPF patients with GERD. Despite the ambiguity, the recognized relation between GERD, microaspiration, and IPF means that antioxidant therapy could be considered as an initial step in IPF treatment. Antioxidant supplementation could alleviate chronic lung injuries from microaspiration and reduce harmful ROS-related processes in both the esophagus and in the lung tissue. The following sections further discuss how antioxidants might represent a targeted approach to addressing shared pathological ROS and inflammation-mediated processes in cases of IPF associated with GERD.
ANTIOXIDANT TREATMENT FOR GASTROESOPHAGEAL REFLUX DISEASE
In view of the increased prevalence of GERD in IPF patients, guidelines recommend that clinicians not only prescribe antifibrotic agents but also PPIs, as a combined first-line treatment [1,14,56,57]. However, studies in GERD patients have demonstrated that PPIs are not a completely effective treatment, as approximately 20–30% of patients still experience troublesome symptoms [58,59]. The problem of overprescription of PPIs should not be ignored. What is more, the large number of side-effects attributed to PPI treatment in GERD is worrying. PPI use is strongly associated with deficiencies of essential micronutrients like vitamin B12, iron, and magnesium, increased risk of calcium supplement malabsorption in women [17,18] bone fractures , kidney and liver disease , and drug–drug interactions [62▪]. PPI use predisposes patients to community-acquired pneumonia  and may alter the composition of the gut microbiota, reducing its diversity, which is associated with poorer health . An especially problematic side-effect of PPI treatment in already vulnerable IPF patients is the increased risk of bacterial infection, because of reduced effectiveness of the gastric barrier [16,17,65].
In view of the available evidence that ROS participate in GERD development, and the presence of disturbances of the innate antioxidant defense system, treatment with pharmacotherapeutic agents for gastric acid suppression alone to alleviate GERD symptoms should be reconsidered or complemented with other approaches. The following section further describes currently available scientific evidence for the suggested alternative GERD treatment with dietary antioxidant supplementation. Quercetin is one of the polyphenol antioxidants that has been most intensively studied for its therapeutic properties, and is highly abundant in plant sources (e.g., apples, berries, onions, tea [66,67]). However, studies have commonly used quercetin food supplements rather than foods. In-vitro studies demonstrated that quercetin is a potent scavenger of ROS and reactive nitrogen species, whereas the few available in-vivo studies attributed to quercetin antiinflammatory and antioxidant activities in diseases involving ROS . Evidence for quercetin is also available from studies investigating its antioxidant effect on GERD. Table 2 highlights the main findings from animal research in regard to quercetin and other antioxidants commonly used in the treatment of GERD [12,69–72].
Given that the scientific literature on animal models supports the beneficial effect of food-derived antioxidant compound supplementation in GERD, it could be postulated that in cases where IPF is associated with GERD, antioxidants could be recommended to alleviate at least some of GERD-related symptoms.
ANTIOXIDANT TREATMENT FOR IDIOPATHIC PULMONARY FIBROSIS
As current evidence suggests that both ROS and an impaired endogenous antioxidant defense system may be involved in the development of IPF, more attention should be given to an alternative treatment that could successfully address these pathological mechanisms of IPF. A growing number of research articles suggest that exogenous antioxidant supplementation could be an approach worth considering for the future treatment of IPF. Antioxidant supplements could complement the inadequately working lung antioxidant defense system and reduce oxidative stress , and furthermore act as antiinflammatory agents . Antioxidant activity is exhibited by both food-derived antioxidant compounds and drugs. In-vivo studies have demonstrated the effectiveness of the antioxidant drug N-acetylcysteine (NAC) in preserving vital functions of the lung in IPF patients, when used together with standard treatment . Despite the possible positive effect of NAC treatment, however, it could not inhibit further disease development or improve survival rates when used alone [20,74]. However, in some cases of early-stage IPF, or in combination treatment with antifibrotic agents, it might reduce the symptoms and slow down the progression of the disease [3▪]. A similar conclusion, that is, that combined antioxidant therapy was safer and more effective than monotherapy, was drawn by Kandhare et al., who performed a metaanalysis on antioxidant treatment (NAC and lecithinized superoxide dismutase) in IPF patients. Quercetin is another potent antioxidant used in studies of IPF, and the main studies regarding its positive effect on IPF are highlighted in Table 3[20,76–78,79▪,80▪,81▪].
Overall, current knowledge about antioxidants regarding their specific beneficial role in IPF suggests that they can be optimistically recognized as an alternative IPF treatment option, potentially effective for a group of IPF patients.
The pathogenesis of IPF is complex, and adequate treatment options are still lacking to improve the condition and increase the survival rates of IPF patients. Therefore, complementary treatment options are crucial, and IPF patients would most likely benefit from a personalized approach in which antioxidant supplementation could complement standard IPF treatment, especially in IPF associated with GERD. Antioxidants have been shown to have beneficial effects in GERD, as well as in reducing IPF progression. However, no studies have investigated the antioxidant effect for both conditions together. Shared effects of antioxidant supplementation for both conditions have been observed in the form of alleviation of chronic lung injury caused by microaspiration, reduction of harmful effects of increased ROS formation (Fig. 1), improvement of the endogenous antioxidant defense system in the esophagus and the lung, and also the reduction of gastric acid production. The flavonoid antioxidant quercetin, alone or in combination with other antioxidant compounds, and medicinal herbs with quercetin as a component, are the best-researched antioxidant, with the most significant therapeutic effects for both conditions. More research is necessary to evaluate the promising combined antioxidant effect in patients with both GERD and IPF. Nevertheless, it can already be concluded that antioxidants can indeed be an effective complementary treatment option for GERD-associated IPF. It should be noted that the effect of antioxidants in GERD and IPF has been thoroughly studied in animals and in-vitro studies, but that only a few human clinical trials are available. This can also be a potential barrier including and recommending antioxidants for the treatment of IPF, and future follow-up studies in humans are essential. However, it is important to consider that clinical IPF trials may be unfeasible, not only because of the rarity of the disease but also because of the poor health, breathing problems and lack of mobility of IPF patients. Hence, future research to strengthen the currently available evidence for antioxidant effectiveness in GERD-associated IPF could be done by first conducting human trials with GERD patients. Over the last few decades, advances in antioxidant research have been hampered by trends and misconceptions in the general population and the medical community. Antioxidants are still perceived as a controversial topic. Unfortunately, an opportunity to improve one's health status or alleviate the symptoms of deadly diseases like IPF might be missed if such views prevail .
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Conflicts of interest
There are no conflicts of interest.
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