Vasoactive intestinal polypeptide (VIP) is a neuropeptide that functions as a neuromodulator and neurotransmitter. It is a potent vasodilator, regulates smooth muscle activity, epithelial cell secretion, and blood flow in the gastrointestinal tract [1-3].
Vasoactive intestinal peptide (VIP, vasoactive intestinal polypeptide, PHM27) is a short peptide hormone made in the gut, pancreas, and brain of most vertebrate animals including humans. VIP binds to class II G protein-coupled receptors and is known to
increase the breakdown of glycogen in liver and muscle,
lower blood pressure,
relax smooth muscle throughout the GI tract,
stimulate contraction of cardiac muscle (by boosting both heart rate and strength of contractions),
stimulate the secretion of water in various areas of the GI tract,
affect vaginal lubrication,
regulate prolactin release,
protect cartilage,
protect neurons against ischemia and oxidative stress,
affect autonomic nerve function, and
help to synchronize the central nervous system (specifically neurons in the suprachiasmatic nucleus) with light cues for regulating circadian rhythm.
VIP has long been an interest in research for all of the reasons above and more. There is a great deal of scientific literature on this particular peptide, making it nearly impossible to cover all of the many facets of VIP research. Below is a summary of some of the high points, including the most important aspect of VIP research – the finding that it VIP can reduce inflammation and fibrosis in a number of different organs.
As it turns out, one of the primary producers of VIP is the immune nerve fibers in blood vessels of the central and peripheral nervous systems and heart. Additionally, VIP is produced directly by cells of the immune system where it helps to promote Th2-type responses which can reduce inflammation and quiet the immune system. VIP and analogues derived from it have been heavily investigated as potential inflammatory mediators in intestinal disease, heart disease, and neuroinflammatory conditions[1], [2]. The various roles of VIP in immunomodulation: In the setting of inflammatory bowel diseases (IBDs) like Crohn’s and ulcerative colitis, VIP has been found to improve intestinal barrier homeostasis and reduce inflammation driven by Th1 cell actions[3]. This latter approach, in particular, appears to generate T cells capable of producing the inflammation suppressing peptide interleukin-10[4]. In recent years it has become apparent that Th1 inflammation is one of several important pathways in IBD. The benefit of improved intestinal barrier function should not be understated as it is hypothesized to be a contributing cause in the pathogenesis of inflammatory bowel disease. In particular, it is thought that compromised barrier function leads to increased antigenic material in the space between cells where it is more likely to interact with immune cells and set off an inflammatory response. Mitigating antigen presentation to immune cells via improved barrier function secondary to VIP would thus reduce what is believed to be one of the first steps in the cascade of events leading to colitis and severe inflammatory bowel disease[3].
Vasoactive Intestinal Peptide in Lung Function
There are at least two ways in which VIP impacts lung function. In the first mechanism, VIP modulates pulmonary vascular remodeling in response to inflammation. It appears to have this effect though suppression of a peptide call NFAT, which activates T cells and leads to increased inflammation[5]. Consistent with its roll in modulating inflammation in other tissues, VIP appears to control T-cell mediate inflammation in the lungs, a process that heretofore has been difficult to address in models of inflammation. In particular, NFAT suppression may play a very important role in preventing pulmonary fibrosis, the end stage of a number of inflammatory conditions such as COPD, sarcoidosis, etc[6]. Thus, VIP may provide a very useful mechanism for preventing the kind of end stage lung disease that can only be cured by transplant and which often results in serious morbidity and even death. VIP also appears to inhibit the proliferation of smooth muscles in pulmonary tissue. Smooth muscle cell proliferation is one of the long-term consequences of lung inflammation and is a particular problem in bronchial asthma that has been uncontrolled for extended periods[7]. There is hope that VIP will provide a mechanism by which to mitigate the effects of long-term inflammation secondary to asthma. There is also exceptional evidence that the vasodilatory effects of VIP, which are known to help control blood pressure, may have a highly potent effect in pulmonary vasculature. Preliminary research shows that VIP lowers blood pressure significantly in the pulmonary artery, leading to increased cardiac output and improved venous oxygen saturation[8]. While more work remains to be done, there is significant hope that VIP will offer a new modality for improving lung function in the setting of primary vascular conditions.
VIP in Transplants
One of the primary problems with organ transplants is rejection by the body’s immune system. No matter how good the match between donor and recipient, the body mounts a response against transplanted organs that eventually leads to their destruction and failure. Currently, the only solution to this problem is the use of broad-spectrum anti-inflammatory medications. Unfortunately, these drugs can lead to susceptibility to serious infections and have side effects of their own, such as scarring and organ fibrosis, that can limit their use. Research on VIP has revealed that the peptide affects dendritic cells (DCs). DCs are important in the immune response because they help the body to recognize antigens and mount appropriate countermeasures. By reducing DC proliferation and activation, VIP helps to thwart immune responses before they are even mounted. Interestingly, this function seems to favor DCs attached to antigens that are tolerogenic. In other words, VIP selectively inhibits the proliferation of DCs that might cause an autoimmune reaction. This is an area of active research as VIP could potentially reduce transplant rejection with fewer infection-promoting side effects[9]. This could make VIP or an analogue of it the foundation of transplant anti-rejection medicine in the future.
VIP as a Neuroprotectant
The role of VIP in the central nervous system is threefold: neurotransmitter, neurotrophic/neurogenic, and anti-inflammatory/neuroprotectant. As with the intestine, VIP’s role in the CNS begins with maintaining barriers. In this case, the peptide helps to maintain the very critical function of the blood-brain barrier (BBB)[10]. The BBB is a layer of cellular protection between blood vessels and the tissue of the central nervous system. It regulates what enters neurological tissue and thus controls everything from nutrition and oxygenation to immune function. Compromise of the BBB has been implicated in the pathophysiology of multiple sclerosis, encephalomyelitis, and even stroke. VIP has also been shown to regulate the accumulation of beta amyloid in mouse models of Alzheimer’s disease and is known to offer neuroprotective effects in Parkinson’s disease[11], [12]. There is also evidence that VIP is an important neuroprotectant in the developing brain where it helps to ward of excitotoxic white matter damage and improve neuron fatty acid myelination[13]. In the case of Parkinson’s disease, VIP appears to offer a similar benefit as in other inflammatory settings by shifting the immune balance away from inflammatory Th1 responses toward anti-inflammatory Th2 responses[14]. The exact role of VIP in Alzheimer’s disease (AD) is less clear. Research shows that processing of VIP is inhibited in AD with levels of the peptide as well as amino acid byproducts being lower in the brains of people affected by AD[15], [16]. Again, the research is unclear at this point, but infusion of VIP into the brains of mice shows a substantial reduction in beta amyloid levels, proving that the peptide plays an important role in the pathophysiology of the disease. The effects of VIP in protecting the CNS appear to be mediated through VPAC1 and VPAC2 receptors. In both cases, stimulation appears to result in increased secretion of neurotrophic factors like ADNP (activity-dependent neurotrophic factor) and BDNF (brain-derived neurotrophic factor). Both of these peptides help to protect synapses and astrocytes. Source: PubChem
Cardiac Fibrosis
As with lung disease, fibrosis is the end stage of a number of different heart conditions. Cardiac fibrosis leads to a number of serious problems including valve dysfunction, decreases in contractility, changes in cardiac filling, and electrical problems. As in lung disease, cardiac fibrosis is the common end stage of many heart conditions and generally necessitates transplant in order to avoid mortality. To date, most cardiac research has focused on preventing scar formation from occurring. A number of commonly used drugs can, at least to some extent, help to slow the process of cardiac remodeling that leads to scarring. Unfortunately, very few cases are 100% successful and most people experience progressive fibrosis and decline in cardiac function. Recent research in rats, however, indicates that VIP may not only slow fibrosis down, but can reverse scarring. It appears that at least part of this effect is mediated through a massive reduction in angiotensinogen and angiotensin receptor type 1a expression. This makes sense as angiotensin receptor blockers and ACE inhibitors have long been known to slow down cardiac modeling/fibrosis and are in fact the first line of prevention for fibrosis[17]. Source: ScienceDirect
Vasoactive Intestinal Peptide and COVID 19
An interesting recent development out of Switzerland and the United States indicates that a synthetic version of VIP called aviptadil (RLF-100) may help to alleviate the lung complications in severe cases of Covid 19. Aviptadil, like VIP, inhibits pro-inflammatory cytokine production. In the lungs, this translates into protection of type-2 alveolar cells, the cells responsible for the bulk of oxygen exchange that takes place in the lungs. In fact, it appears that Aviptadil may actually prevent the SARS-2 coronavirus from penetrating these cells and infecting them. There are currently ongoing phase 2/3, placebo-controlled trials to investigate the effectiveness of this VIP derivative in protecting against serious complications of COVID 19[18]. According to Dr. Jonathan Javitt, CEO of NeuroRX (NeuroRX has paired with the maker of aviptadil to expedite development and use of the drug in the treatment of COVID), rapid recovery is seen in patients on ventilators and ECMO just three days after treatment with RLF-100. This is even that case in patients with severe medical comorbidities. The drugs has been administered on an emergency basis to patients too ill to be admitted to the clinical trial. Dr. Javitt points out that no antiviral agent has demonstrated the kind of rapid recovery from infection and demonstrated inhibition of viral replication the way that Aviptadil has.
Vasoactive Intestinal Peptide and COVID 19
VIP is a member of a much larger group of neuro and endocrine peptides. It has been shown to have a number of effects in relation to the central nervous system, GI tract, pulmonary tissue, and immune system. It is known to play an active role in embryonic growth and development. Research shows that VIP can help to reduce inflammation throughout the body, but that it is particularly useful in the setting of neurodegenerative disease, pulmonary fibrosis, inflammatory bowel disease, and cardiac fibrosis. The peptide appears to be highly effective in a number of fibrotic pathways and may offer treatment benefits in the common process of fibrosis that leads to so much morbidity and mortality. In addition to its antifibrotic effects, which appear to be mediated through anti-inflammatory actions, VIP is also a potent immune system regulator and general anti-inflammatory. The peptide has also been shown to protect the central nervous system against insult and is of active interest for its ability to preserve cognitive function in the setting of neurodegenerative disease.
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