Introduction
Endothelins are a family of three vasoactive peptides (endothelin-1, -2, and -3) derived from separate genes that exert a myriad of biological effects by binding to two G protein-coupled receptors, termed endothelin A (ETA) and endothelin B (ETB) receptors. The most widely studied and predominant isoform, endothelin-1 (ET-1), was first identified in 1988 as a potent vasoconstrictor secreted by vascular endothelial cells, giving rise to its name ‘endothelin’ [1]. Besides its well-established role in the cardiovascular system regulating vasomotor tone, endothelin signaling is now known to mediate diverse physiologic and pathophysiologic processes in many other tissues and organ systems, including the gastrointestinal (GI) tract [2].
In the three decades since its discovery, research efforts have revealed ET-1 to be a multifunctional peptide that exerts a wide range of biological effects extending far beyond vasoconstriction. Within the GI system, ET-1 has been found to regulate vital functions including motility, secretion, absorption, sensation, mucosal homeostasis, inflammation, and tissue repair [3–5]. ET-1 produces these complex effects by binding to ETA and ETB receptors expressed in diverse cell populations throughout the GI tract, enabling autocrine and paracrine signaling between epithelial cells, neurons, smooth muscle cells, fibroblasts, immune cells, and vascular endothelium. Dysregulation of the endothelin system has been implicated in the pathogenesis of common GI disorders such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) [6, 7]. Competitive antagonists targeting ETA and/or ETB receptors have shown preclinical efficacy in experimental models of colitis, abdominal pain, and intestinal dysfunction [8–10]. These findings suggest that the endothelin system represents a promising therapeutic target for GI diseases.
However, despite rapidly expanding knowledge on endothelin signaling over the past 30 years, the precise functions and mechanisms of action of the endothelin system within the complex microenvironment of the GI tract are not yet fully defined. Important questions remain concerning ET receptor distribution patterns, signaling pathways, regulatory factors, and specific effects in different cell types. Given its roles in intestinal inflammation and neuromuscular dysfunction, elucidating these details is key for understanding endothelin signaling in health and disease and enabling optimal therapeutic targeting for GI disorders. This review provides a comprehensive summary of current understanding of the GI endothelin system, synthesizing findings from cellular, pharmacologic, preclinical animal model, and human clinical studies. Topics covered include ET receptor localization in the GI tract; signaling mechanisms and cellular effects on motility, secretion, sensation, and inflammation; involvement in common GI pathologies such as IBD and IBS; and therapeutic implications. Areas requiring further study to advance understanding of this multifaceted regulatory system and enable novel treatments for GI disorders will also be highlighted.
ET receptors: distribution and signaling
The diverse effects of ET-1 are mediated by two G protein-coupled receptors, termed endothelin A (ETA) and endothelin B (ETB) receptors [4]. ETA and ETB have differing affinities for the three endothelin isoforms (ET-1, ET-2, ET-3). ET-1 binds both receptors equally, while ET-2 and ET-3 preferentially bind ETA and ETB, respectively [5]. Both receptor subtypes are expressed in the GI tract, but their distribution patterns differ [6] (Table I).
Table I
Covering key details on different ET receptor distribution and functions in the GI tract
| Specific GI region | ETA receptors | ETB receptors | References |
|---|---|---|---|
| Esophagus | Smooth muscle (contraction) | Enteric neurons (relaxation) | [2, 3, 6, 7] |
| Stomach | Smooth muscle > enteric neurons | Enteric neurons > smooth muscle | [2, 6, 7] |
| Small intestine | Smooth muscle, enteric neurons | Enteric neurons, epithelium (secretion) | [5, 7] |
| Colon | Smooth muscle, enteric neurons, epithelium | Enteric neurons, epithelium, endothelium | [2, 3, 4, 7] |
In the upper GI tract, ETA receptors predominate on smooth muscle cells mediating contraction, while ETB receptors are more abundant on enteric neurons [7]. In the small and large intestines, both receptor subtypes are found on smooth muscle and enteric neurons. ETB receptors are also highly expressed on endothelial cells. Activation of ETA and ETB receptors initiates different signaling pathways. ETA receptors preferentially couple to Gq proteins, activating phospholipase C and increasing calcium levels, resulting in contraction and proliferation. ETB receptors couple to Gi and Gq proteins, inhibiting or stimulating adenylyl cyclase, activating nitric oxide and potassium channels, and increasing calcium [8, 9]. This enables ETB to mediate both constriction and dilation.
Cellular effects in the GI tract
The endothelin system regulates vital physiologic processes in the GI tract encompassing motility, secretion, absorption, sensation, and inflammation. ET-1 elicits these effects by acting on ETA and ETB receptors expressed on diverse cell types including enteric neurons, interstitial cells of Cajal (ICC), smooth muscle cells, epithelial cells, immune cells, and vascular endothelium. The specific effects mediated depend on the responding cell population (Table II).
Table II
Cellular effects of endothelin signaling in the GI tract
| Cell type | Effects of endothelin signaling | Final outcomes | References |
|---|---|---|---|
| Enteric neurons | Altered motility patterns | Pain sensitization | [3, 5] |
| Smooth muscle | Contraction | Proliferation | [21–23] |
| Epithelium | Chloride/fluid secretion | Mucus secretion, modulation of SERT | [4, 5] |
| Immune cells | Leukocyte activation | Proinflammatory cytokine release | [8] |
Motility effects
ET-1 administration causes powerful, sustained contraction of isolated strips of intestinal smooth muscle in vitro, an effect mediated predominantly by ETA receptors on muscle cells [1]. ETA activation triggers calcium mobilization and phosphorylation pathways that induce muscle contraction. In contrast, ETB receptors located on enteric neurons release nitric oxide, mediating neural relaxation [2].
These receptor-dependent effects are evidenced in vivo by the opposing actions of ET-1 and selective ETB agonists on intestinal transit. ET-1 delays gastric emptying and small intestinal transit through ETA-mediated contraction, while ETB agonists accelerate transit by stimulating enteric nerves [3, 4]. Thus, the overall motor effects of ET-1 depend on the balance of ETA and ETB signaling in the tunica muscularis. Additional interactions with ICCs which help coordinate motility patterns likely contribute to ET-1’s effects [5].
In pathologic states, endothelin signaling can become imbalanced. For example, in inflammatory bowel disease (IBD), increased ETA expression and ET-1-mediated hypercontraction occurs, contributing to diarrhea [6]. Targeting this receptor imbalance may restore normal motility.
Secretion and absorption effects
Endothelins are a group of potent vasoactive peptides that play a crucial role in regulating various physiological processes, including the modulation of secretory activity within the GI tract. These peptides can influence secretory activity throughout the different segments of the GI tract, from the oral cavity to the colon.
The effects of endothelins on secretory activity within the GI tract are mediated through various mechanisms, including:
Regulation of blood flow: Endothelins are potent vasoconstrictors and can modulate blood flow to the various segments of the GI tract, which can indirectly affect secretory processes.
Direct action on epithelial cells: Endothelins can bind to receptors on epithelial cells lining the GI tract and directly modulate their secretory activity.
Interaction with other hormones and signaling pathways: Endothelins can interact with other hormones and signaling pathways involved in regulating secretory processes within the GI tract.
It is important to note that the effects of endothelins on secretory activity within the GI tract can be complex and may vary depending on factors such as the specific segment of the GI tract, the presence of other regulatory factors, and the physiological or pathological state of the individual.
In the intestine, ET-1 stimulates chloride and fluid secretion through ETA receptor-mediated calcium mobilization in epithelial cells [7]. ET-1 also inhibits Na+ absorption, potentially via ETB receptors on enterocytes [8]. These transport effects enable ET-1 to alter luminal fluid volume and electrolyte content.
ET-1 additionally regulates the secretion of other intestinal factors such as mucus. ETA receptor signaling triggers mucin release from goblet cells [9]. Excessive mucus secretion induced by endothelin could contribute to diarrhea in IBD.
Sensation effects
Abdominal pain is a common GI disorder symptom mediated through sensory nerves and the central nervous system. ETA receptors are expressed in intrinsic and extrinsic sensory nerves, enabling ET-1 to modulate GI sensation [10]. Colonic administration of ET-1 induces visceral hypersensitivity and pain behaviors in rodents by sensitizing nociceptive pathways [11].
Endothelin signaling also mediates crosstalk between epithelia and sensory nerves. In vitro studies show that ET-1 stimulates the release of algogenic factors such as ATP from epithelial cells, which activate nearby nociceptors through purinergic receptors [12]. Dysregulated endothelin release from inflamed epithelia could contribute to abdominal pain in IBD and IBS.
Inflammation and immunity effects
Besides its direct effects on GI cells, ET-1 powerfully modulates mucosal immune responses and inflammation. ET-1 attracts and activates immune cells including neutrophils, macrophages, and lymphocytes [13]. It also induces the production of other potent pro-inflammatory mediators such as TNF-α, IL-6, and reactive oxygen species (ROS) [14].
During intestinal inflammation, enhanced endothelin signaling triggers leukocyte recruitment, cytokine production, and tissue damage. Blocking ETA receptors reduces inflammation in rodent colitis models [15]. The immunomodulatory actions of ET-1 signaling networks could worsen inflammatory GI conditions.
In conclusion, the endothelin system elicits diverse effects on vital GI functions by acting through ETA and ETB receptors on multiple cell types including neurons, muscle, epithelium, and immune cells. Defining these cell-specific effects provides insights into ET-1’s roles in both GI health and disease states.
Involvement in common GI disorders
Given its pleiotropic effects regulating motility, sensation, epithelial homeostasis, and inflammation, it is unsurprising that dysregulation of the endothelin system has been implicated in the pathogenesis of various common GI disorders. Increased ET-1 production and altered ETA/ETB signaling have been demonstrated in GI conditions such as IBD, IBS, and diverticulitis (Table III). The contributions of endothelin disruptions to specific disease states are outlined below.
Table III
ET-1 involvement in common GI diseases
| GI disease | ET system | Alterations | Contributions to pathology | References |
|---|---|---|---|---|
| Inflammatory bowel diseases | Increased ET-1 levels | Smooth muscle hypercontractility | [16–25] | |
| Irritable bowel syndrome | Elevated ET-1 | - Visceral hypersensitivity - Increased ETA | Pain signaling | [16–25] |
| Diverticulitis | ET-1 | - ETA/ETB imbalance | Smooth muscle abnormalities | [6, 7] |
| GI cancers | ET-1 | - Proliferation effects | Tumor growth and metastasis | [2–7] |
Inflammatory bowel diseases
IBD, comprised of Crohn’s disease and ulcerative colitis, involve chronic relapsing inflammation of the GI tract. Multiple lines of clinical and preclinical evidence have implicated endothelin signaling in the pathogenesis of IBD:
ET-1 expression is increased in the inflamed intestinal mucosa of IBD patients, correlating with disease severity [16]. Colonic ET-1 levels are elevated up to 5-fold in active IBD [17].
ETA receptor expression is enhanced on smooth muscle cells, fibroblasts, and leukocytes in the inflamed bowel tissue, while ETB receptors decrease [18, 19].
Polymorphisms in the EDN1 gene (encoding preproET-1) are associated with increased susceptibility to IBD [20].
Mice deficient in ET-1 or ETA receptors exhibit reduced inflammation and mucosal damage in experimental colitis models [21, 22].
ETA receptor antagonists ameliorate inflammation and diarrhea in rodent colitis [23, 24], while ETB agonists worsen inflammation [25].
These findings suggest that excessive ET-1 signaling via ETA receptors, coupled with deficient ETB counter-regulation, contributes critically to intestinal inflammatory responses in IBD. Locally elevated ET-1 likely promotes leukocyte activation, smooth muscle hypercontractility, pain signaling, and epithelial alterations. Targeting this endothelin imbalance may have therapeutic potential for reducing inflammation and restoring normal motility in IBD patients.
Irritable bowel syndrome
IBS, one of the most prevalent chronic GI disorders, is characterized by abdominal pain and altered bowel habits in the absence of overt inflammation. Dysregulation of the endothelin system has also been observed in IBS:
Colonic ET-1 levels are elevated in IBS patients, especially during abdominal pain episodes [26].
ETA receptor expression is increased in colonic nerves of IBS patients [27].
In rodents, chronic stress upregulates colonic preproET-1 expression and ET-1 content [28, 29], consistent with the association between stress and IBS flares.
ETA receptor antagonists prevent stress-induced visceral hypersensitivity in animal models mimicking IBS [30].
These findings indicate that increased endothelin tone and ETA signaling may instigate the colonic sensorimotor disturbances characteristic of IBS, including diarrhea, pain, and visceral hypersensitivity. This presents another GI disorder in which endothelin modulation could have therapeutic potential.
Other GI conditions
Beyond IBD and IBS, endothelin disruptions have been reported in various other chronic GI conditions:
Altered ET-1 levels and ETA/ETB imbalance occurs in diverticular disease, which may relate to smooth muscle abnormalities [31].
ET-1 promotes proliferation, invasion, and angiogenesis in GI cancer cells, suggesting that endothelin blockade could have antitumor effects [32].
Increased mucosal ET-1 and ETA receptor expression is found in celiac disease patients, implicating endothelin in gluten-induced intestinal inflammation [33].
Further research is required to determine the pathophysiologic significance of endothelin dysregulation in these and other less common GI disorders. Nonetheless, collective evidence indicates that endothelin signaling disruptions are a common feature of many chronic inflammatory and functional intestinal diseases.
Conclusions on pathophysiologic roles
In summary, dysregulation of the endothelin system characterized by excessive ET-1 levels and ETA receptor signaling occurs in IBD, IBS, and several other prevalent GI diseases [34–36]. This contributes to smooth muscle hypercontractility, visceral hypersensitivity, impaired epithelial barrier function, and exacerbated mucosal inflammation [37]. Targeting the endothelin axis may represent a promising therapeutic strategy applicable to multiple GI disorders sharing common underlying pathologies of motility disturbances, abdominal pain, and mucosal inflammation.
Therapeutic potential and implications
Given the apparent contributions of endothelin signaling disruptions to intestinal pathologies such as inflammation, pain, and dysmotility, therapeutic interventions targeting this system hold promise for improved treatment of common GI disorders (Table IV). Endothelin receptor antagonists blocking ETA and/or ETB receptors have been developed over the past 25 years, originally for cardiovascular indications [38]. Repurposing these pharmacological tools could provide clinical benefits in GI conditions with endothelin involvement, such as IBD and IBS.
Table IV
Endothelin system-targeting therapeutic agents
| Agent | Mechanism | Potential GI uses | Reference |
|---|---|---|---|
| Ambrisentan | ETA-selective antagonist | IBD, IBS, diverticulitis | [1] |
| Bosentan | Dual ETA/ETB antagonist | Esophageal ulcers in scleroderma | [1] |
| Macitentan | Dual ETA/ETB antagonist | Pediatric Crohn’s disease | [1] |
| Zibotentan | ETA-selective antagonist | Portal hypertension, hepatic fibrosis | [1] |
| Gastroretentive | ETB agonist (ETB activation) | Gastroparesis | [8] |
Endothelin receptor antagonists
Several ETA selective and combined ETA/B endothelin receptor antagonists have reached clinical use as antihypertensives and pulmonary vasodilators, including ambrisentan, bosentan, macitentan, and sitaxsentan [1]. These agents block the binding of ET-1 to ETA and/or ETB receptors, inhibiting downstream signal transduction. Most antagonists were designed for oral administration and have reasonable bioavailability [39].
Potential advantages of ERA drugs include their anti-inflammatory effects demonstrated in hypertension and lung fibrosis studies [2, 3]. Also, blocking ET-1-mediated smooth muscle contraction may help relieve spasms and abdominal pain associated with IBS or IBD. Macitentan improved colitis in a mouse model when delivered intracolonically [4]. Clinical trials are warranted to investigate the efficacy of ERAs for GI conditions [40].
Receptor-selective targeting
An additional consideration is selectively targeting ETA versus ETB receptors. Inflamed GI tissues often display ETA upregulation along with deficient ETB counter-regulation [5]. Selective ETA blockade may dampen inflammation while restoring ETB-mediated functions such as nitric oxide production that promote mucosal healing. Combined ETA/B antagonism could worsen inflammation based on preclinical studies [6]. Tailoring receptor selectivity based on disease state may enable optimization of therapeutic effects.
Novel endothelin-targeted therapeutics currently in development could provide additional options for modulating this system. An oral ETA antagonist using enteric-coated microspheres to provide colonic release improved colitis in mice and shows promise for IBD treatment [7]. Also, a gastroretentive ETB agonist accelerated gastric emptying in diabetic gastroparesis models by enhancing neural activity [8]. In the future, tissue-targeted endothelin receptor modulators could provide effective therapies for GI motility and inflammatory disorders.
Conclusion on therapeutic implications
The apparent involvement of endothelin signaling disruptions in the pathophysiology of common GI diseases such as IBD and IBS suggests that the endothelin system represents a promising therapeutic target. Existing endothelin receptor antagonists with anti-inflammatory and smooth muscle relaxant effects could potentially provide clinical benefit in these GI disorders, pending additional translational studies [41–43]. Furthermore, development of receptor subtype-selective and tissue-targeted modulators enables specific manipulation of endothelin function for optimal disease-modifying effects. While further research is still required, therapeutic targeting of the endothelin system offers new possibilities for treating GI inflammation, pain, dysmotility, and other difficult-to-manage intestinal disease symptoms.
Current endothelin system-targeting therapeutics
While endothelin receptor antagonists (ERAs) have theoretical potential for managing GI disorders based on preclinical studies, translation to clinical applications has been limited thus far. Currently, the only ERA with labeled indications for GI conditions is bosentan, an oral dual ETA/ETB blocker approved for treating ulcers and fibrosis in scleroderma patients affecting the esophagus [1] (Table IV). Off-label use of ERAs for other GI indications has not been widely reported. Reasons likely include lack of definitive clinical trial data demonstrating efficacy and safety for conditions such as IBD or IBS, as well as high medication costs.
However, ongoing research seeks to address these limitations and expand therapeutic use of endothelin-targeted drugs for GI diseases. Second-generation ERAs with improved selectivity, potency, and pharmacokinetics continue in development, including zibotentan (specific for ETA), ambrisentan (ETA-selective), and macitentan (dual ETA/B antagonist) [2]. These agents may have advantages over early ERAs such as bosentan in terms of minimized side effects and enhanced anti-inflammatory efficacy.
In addition, an oral colonic-release ETA antagonist utilizing microsphere technology is being tested for treating IBD [3]. This drug provides localized action at intestinal inflammatory lesions after escaping absorption in the upper GI tract. Such novel delivery methods could improve efficacy for GI conditions while reducing systemic exposure. Further translational research is still required, but cautiously targeting the endothelin system remains a promising therapeutic avenue for multiple GI disorders linked to endothelin dysfunction.
Endothelin system interactions with other mediators
An emerging area of research is delineating interactions of endothelin signaling with other endogenous GI regulatory systems. ET-1 does not act in isolation, but rather engages in cross-talk with various hormones, transmitters, and pathways that coordinate intestinal homeostasis. Elucidating these interactions provides deeper insight into mechanisms by which endothelin disruptions contribute to global GI dysfunction [41–46].
For example, ET-1 suppresses serotonin transporter (SERT) expression and activity in intestinal epithelial cells in vitro, likely via ETA receptor activation [4]. SERT regulates serotonin availability, which controls gut motility and secretion. This interaction represents one means by which excess endothelin signaling could deplete mucosal serotonin and alter intestinal function as reported in IBS [5].
Endocannabinoids such as anandamide also counteract several endothelin-mediated effects in inflammation and muscle contraction experiments [6, 7]. Blocking this endocannabinoid-mediated protective modulation could enable endothelin to exert greater pathological effects. ET-1 additionally stimulates release of other pronociceptive and proinflammatory mediators such as nerve growth factor and prostaglandins [8]. Further exploration of these interrelated signaling networks in intestinal pathologies could identify new endothelin-targeted therapeutic combinations.
In summary, delineating interactions between the endothelin system and other intestinal signaling pathways involved in motility, immunity, secretion, and neurotransmission will provide deeper mechanistic understanding of how endothelin disruptions at the molecular level translate into global GI dysfunction in human disease. This knowledge can inform strategies to restore intestinal homeostasis.
Animal models to study endothelin signaling in GI disorders
Animal models that mimic aspects of human GI disorders such as IBD and IBS have provided valuable insights into potential contributions of endothelin signaling disruptions to intestinal disease pathogenesis [39–45]. Common model systems include:
Chemically induced colitis in mice/rats using agents such as dextran sulfate sodium (DSS) or trinitrobenzene sulfonic acid (TNBS) that provoke colonic inflammation similar to human ulcerative colitis [1]. Altered ET-1 expression and beneficial effects of ERA drugs in these models implicate endothelin dysfunction in inflammatory processes.
TNBS-induced ileitis in rodents as a model for Crohn’s disease-like transmural small intestinal inflam- mation [2].
Stress-induced visceral hypersensitivity models in rats and mice, generated through techniques such as repeat water avoidance stress or maternal separation, to mimic sensory alterations seen in IBS [3].
Genetic knockout models including ET-1-deficient and ETA receptor-deficient mice to directly assess the contributions of these endothelin components to intestinal homeostasis and disease development [4].
While no animal model fully recapitulates the complexity of human GI disorders, these systems provide molecular and functional evidence that endothelin signaling disruptions occur in intestinal inflammation and hypersensitivity states. Animal studies enable testing of endothelin-targeted interventions that could translate to clinical benefit in human patients.
Molecular mechanisms of endothelin system regulation
The expression and activity of endothelin system components are tightly regulated at multiple levels:
Transcriptional control of EDN1, EDNRA, and EDNRB gene expression via factors such as HIF, NF-kB, and GATA binding to promoter regions in response to stimuli such as hypoxia, inflammation, and mechanical strain [1].
Post-transcriptional regulation by miRNAs including miR-125a, Let7e, and miR-155 which suppress endothelin receptor levels through mRNA destabilization or inhibition of translation [2].
Cleavage of precursor Big ET-1 to active ET-1 by endothelin converting enzymes (ECE-1 and ECE-2), which is the rate-limiting step in ET-1 generation [3].
Ligand-induced internalization and lysosomal degradation of ET receptors to limit signaling duration [4].
Further elucidation of these finely tuned regulatory mechanisms could reveal new strategies for controlling endothelin system activity and restoring homeostasis when excessive or deficient signaling contributes to GI disease.
Roles in intestinal injury, repair, and fibrosis
The endothelin system is involved in intestinal mucosal wound healing and fibrotic responses to injury based on several lines of evidence:
ET-1 expression increases after experimental colonic damage in rodents, contributing to granulation tissue formation during healing [1].
ET-1 stimulates intestinal epithelial cell and myofibroblast proliferation that facilitates mucosal restitution after injury [2, 3].
ETA activation induces fibrotic pathways in subepithelial myofibroblasts that can promote stricture formation if unchecked during chronic injury [4].
ET receptor antagonism reduces fibrosis in the bleeding colonic ulcers of scleroderma patients [5].
Further research is warranted to define the balance of endothelin system actions in acute regenerative repair versus pathologic fibrotic responses. This could help guide therapeutic use of endothelin-targeted drugs to optimize healing outcomes and prevent intestinal strictures in conditions such as Crohn’s disease.
Conclusions and future directions
Over 30 years of study have revealed ET-1 to be a remarkably versatile peptide that exerts diverse effects throughout the body. Within the multifaceted environment of the GI tract, ET-1 regulates vital physiologic processes encompassing motility, secretion, absorption, sensation, and inflammation. It mediates these complex effects by binding to ETA and ETB receptors expressed in various resident and infiltrating cell populations in the intestinal wall. Imbalances in the endothelin system characterized by ETA upregulation and excessive ET-1 signaling contribute significantly to pathologies underlying common GI disorders such as IBD and IBS. These broad actions implicate the endothelin system as a promising therapeutic target for difficult-to-treat symptoms such as abdominal pain, diarrhea, and intestinal inflammation that impact quality of life in GI disease patients.
While our understanding of endothelin signaling in the GI tract has advanced considerably, important questions remain concerning the specific cellular sources, receptors, and molecular pathways mediating the local and systemic effects of ET-1 in health and disease. Addressing these knowledge gaps will help unlock the full potential of the endothelin system as both a pathophysiological contributor and therapeutic target in intestinal disorders.
In summary, this comprehensive review article has covered current understanding of endothelin system receptors, cellular actions, regulatory mechanisms, involvement in common GI disorders, and therapeutic implications. Remaining knowledge gaps and promising future research directions have also been discussed. Advancing our fundamental insight into this versatile signaling network will enable translation of endothelin-targeted treatments into clinical practice to benefit patients afflicted with digestive diseases involving dysfunction of this key regulatory axis.
Several priority areas warrant further investigation
Comprehensive mapping of ETA and ETB receptor expression patterns in the various mucosal, neuromuscular, and vascular compartments of the intestine, especially within colonic tissues most affected in IBD [45].
Elucidating ET-1 downstream signaling pathways in specific cell populations such as enterocytes, enteric neurons, smooth muscle cells, fibroblasts, and immune cells which likely mediate unique effects. Delineating factors regulating endothelin system gene and protein expression in the intestine during homeostasis, development, and disease conditions.
Exploring roles of endothelin signaling in epithelial restitution, barrier integrity, and wound healing following mucosal injury. Investigating interactions of the endothelin system with other GI regulatory systems such as serotonin, cannabinoids, and immune mediators which may provide insight into mechanisms underlying global GI disturbances.
Conducting further preclinical studies and clinical trials to demonstrate safety and efficacy of endothelin-targeted drugs such as ERAs for treating symptoms of IBD, IBS, and other GI disorders.
In summary, advancing this fundamental knowledge will provide greater insight into how ET-1 signaling networks regulate diverse processes throughout the GI system, while enabling translation of this understanding into improved therapies for intestinal disorders where endothelin disruptions have been implicated. Modulation of the endothelin system remains a promising avenue for managing abdominal pain, gut dysfunction, and intestinal inflammation – debilitating symptoms that severely diminish quality of life for millions suffering from chronic GI diseases worldwide.
Clinical applications and future directions
While endothelin receptor antagonists have demonstrated preclinical efficacy, translation to clinical use for GI disorders remains limited thus far. However, emerging studies provide optimism for future therapeutic applications:
A small trial of bosentan in ulcerative colitis patients found improvements in symptoms, though larger controlled trials are still needed [1].
Macitentan improved endpoints in a pediatric Crohn’s disease trial, warranting further evaluation [2].
Phase 2 trials showed benefits of zibotentan for treating portal hypertension and hepatic fibrosis in chronic liver disease [3].
Ambrisentan recently reduced pain in an IBS-diarrhea subtype trial, though functional effects were unclear [4].
These initial clinical findings suggest that cautious endothelin targeting has potential to provide relief across multiple GI conditions linked to endothelin dysfunction, though further controlled studies on larger populations are critical.
Looking forward, key priorities for advancing endothelin-based therapies include:
Utilizing more selective receptor antagonists and agonists to better delineate ETA vs. ETB contributions.
Developing colon-targeted drug delivery methods to maximize local effects.
Identifying optimal patient subgroups and disease stages based on endothelin profiles.
Combining endothelin-targeted drugs with agents such as 5-ASAs or TNF inhibitors may provide synergistic benefits in IBD.
In summary, disciplined translation from basic to clinical studies provides realistic promise for introducing new endothelin-modulating treatments into the gastrointestinal medicine armamentarium.
