Inflammation in Pulmonary Hypertension – A Scientific Perspective, with a focus on Hypoxic PH

What is inflammation?

Inflammation is a complex biological response of the body to remove foreign objects like pathogens (bacteria, virus, fungus), damaged cells, or irritants. It involves cells of the immune system, blood cells, tissue cells, and chemical mediators such as cytokines, chemokines, and reactive oxygen species. We typically have negative connotations associated with inflammation, which is justified, but not all cases of inflammation are negative. We need inflammatory processes to remove harmful pathogens, damaged cells or irritants. The problem arises when this inflammation goes unresolved, and becomes a chronic condition.

There is another common harmful side of the immune system, however. One with negative connotations that are well justified. That is, our immune system can be activated to “attack” our own cells. Cells of the immune system can be thought of as guard dogs. Early in the course of the growth and development of each individual, a process takes place that “conditions” the guard dogs of the immune system to attack only foreign objects, and not our healthy cells. Sometimes, however, this process goes awry, and this gives rise to the guard dogs sniffing our own cells and mistaking them for invaders, thus giving rise to autoimmunity. The presence of autoimmunity can also occur, however, via interaction with foreign objects (typically proteins on cell surfaces) that look very similar to our own proteins. Thus when the guard dog encounters this look-alike protein, it senses something different, and attacks it, but since it is similar to our proteins, the guard dog eventually has a hard time differentiating between the healthy cells and the similar looking foreign objects. That is how autoimmunity can arise.

In sum, inflammation is a protective mechanism, but when unresolved or when directed at the wrong culprit (i.e. our healthy cells), it can lead to chronic inflammation and unwanted conditions such as heart disease, lung disease, cancer, and autoimmunity.

What about in the context of a rare syndrome such as pulmonary hypertension (PH)?

PH takes on many different forms (hypoxia induced, lung disease induced, etc.), and in most cases such as idiopathic PH (IPAH), the underlying cause is unknown. It is well known that there is a large component of chronic inflammation observed in PH. Whether this inflammation is present as a cause or consequence of PH has yet to be determined. We do know however, that a large portion of patients with autoimmune conditions like Rheumatoid Arthritis and Scleroderma, eventually develop PH, or have a higher likelihood of developing PH than normal. This clues us in to the fact that there may be an autoimmune component, or at least some type of inflammatory process, that is central to PH.

Markers of inflammation, such as activated immune cells (both innate and adaptive), cytokines, chemokines, as well as the presence of reactive oxygen species (ROS) are all present in both the systemic circulation and within the tissue and vasculature of the lung. While each case of PH is different, and the extent and type of inflammation in each form may differ (as well as from patient to patient), there are common underlying features of inflammation in PH that may give us clues to whether inflammation is a cause or consequence of PH. In this article, we will review inflammation in PH as it occurs in the context of hypoxic pulmonary hypertension. The review compiles information from the excellent review article “The Effects of Chronic Hypoxia on Inflammation and Pulmonary Vascular Function” by Stenmark et al. in “Pulmonary Hypertension: Basic Science to Clinical Medicine”.

Inflammation in PH

Regardless of the cause, chronic inflammation is present and is a staple of PH. As discussed above, chronic inflammation could be the result of PH, but it could also be the trigger that causes PH to develop. I believe it is a trigger, and recent evidence (described below) points to this being the case. However, more studies need to be done to confirm this. It also may be the case that, in one form of PH, inflammation is the cause, but in another form, it may be a result of PH as the underlying condition (thus inflammation as a cause or consequence may be “situational” or “categorical” in nature).

Data from both human and animal studies indicate that early and persistent inflammation contributes to pulmonary vascular disease and that the amount of inflammatory infiltrates in the perivascular region (i.e. the area situated or occurring around the blood vessel) correlates with vascular remodeling and hemodynamic parameters in PH. In this case, it is a positive correlation, i.e. you can expect increased inflammatory infiltrates when the markers of vascular remodeling, vascular resistance, vascular pressure, etc. are all high.

One recent and very interesting theory posits that inflammation contributes to pulmonary vascular disease via an “outside-in” mechanism, whereby there is an influx of leukocytes (inflammatory cells) into the adventitia (the outermost layer of the blood vessel) during vascular injuries and/or sustained inflammatory states such as those which occur in PH. We do know this influx occurs, but the origin of these sustained inflammatory states and/or vascular injuries causing this influx could occur in any portion of the blood vessel, the inside (intima) or the outside (adventitia). Regardless, the influx itself in this outside-in fashion (and resulting cross-talk with resident stromal and adventitial cells) helps to contribute to a perpetual increase in pulmonary vascular dysfunction and remodeling, leading to the pathological development of PH.

The sustained inflammatory states mentioned above, creating the outside-in influx of inflammatory cells, can arise due to a hypoxic environment, cytokine release, or persistent immune and vascular cell activation perhaps due to an “off-switch” failure in these cells preventing them from turning off. The influxed leukocytes, along with adventitial fibroblasts, can then penetrate inward into the media (middle) and intima (innermost region) of the blood vessel. Hypoxia, cytokine release, and vascular injury activates these immune and adventitial cells, which can then go on to initiate and perpetuate inflammatory responses within the adventitia, media and intima of the blood vessel. In light of this, it could perhaps be the case that persistent autoimmunity in the lung vasculature or lung tissue creates these sustained inflammatory states and thus attracts leukocytes and fibroblasts from the adventitia all the way into the media. This would occur because autoimmunity could trigger either cytokine release or vascular injury. Either way, if this were the case, than inflammation would be a “cause”. However, in the case of hypoxia and/or other forms of vascular injury, than the sustained inflammatory state is clearly a consequence, thus being sustained only as long as hypoxia (from low-altitudes, or from lung disease) and/or vascular injury persists.

Aside from the cause of the sustained inflammatory state, the mechanism by which this sustained state occurs is thought to be due to a positive feedback loop between A) resident stromal cells (i.e. connective tissue cells) and mesenchymal cells (i.e. stromal stem cells that can differentiate into bone cells, fat cells, muscle cells, etc.) and B) resident/infiltrating cells like macrophages. This feedback loop is thought to be key in driving the persistence of inflammation in diseases such as cancer and PH. What’s more is that once present, inflammation can drive epigenetic changes in innate immune cells, locking them in a state where they experience a loss of functional plasticity and failure to respond to regulatory signals. In particular, inflammation can promote epigenetic marks in fibroblasts and macrophages specifically, switching them into a pro-fibrogenic and pro-remodeling phenotype.

Below we will look into how hypoxia in particular can induce inflammatory states in different portions of the vasculature. As you will see, each section of the vasculature can contribute to inflammation, although it typically is triggered via the very first layer inside the lumen of the blood vessel, or the “intima”.

The Intima: Endothelial Cells (EC’s)

Under hypoxic conditions, pulmonary artery endothelial cells (PAEC’s) obtain a vasoconstrictive phenotype via 1) decreased activity/production of prostacyclin and nitric oxide (NO), and 2) increased production of endothelin, serotonin, and leukotrienes. Hypoxia also causes the release of the following molecules from PAEC’s:

Pro-inflammatory mediators – IL1, IL6, IL8
Pro-mitogenic mediators – VEGF-1, Endothelin-1, Thromboxane, PDGF-B, CXCL1
Anti-thrombic mediators – increased tissue factor, decreased thrombomodulin
Inflammatory cell adhesion molecules – ICAM, VCAM, P-selectin

It is clear from the above, that a multitude of inflammatory mediators and molecules are released from PAEC’s under hypoxic conditions. But if this is the case, then why do we observe inflammatory cells aggregating into adventitia (the “outside-in” hypothesis mentioned earlier) as opposed to directly through PAEC’s? One reason could be that the EC’s of the vasa vasorum, which feeds the adventitia, have the highest expression of inflammatory adhesion cells compared to the other cells in the vasculature. Indeed new evidence is beginning to support this fact, showing that there are distinct interactions between EC’s and inflammatory cells in the EC’s of different organs. This means that it is the EC’s of the blood vessels supplying the outermost layer (i.e. the vasa vasorum) that could be the funnel for the infiltrating leukocytes, in an “outside-in” fashion.

The Media: Smooth Muscle Cells

One of the main reasons for the increased pulmonary vascular resistance that is observed during PH is due to thickening and remodeling of the small pulmonary arteries. The small pulmonary arteries account for the majority of the total cross sectional area in the entire pulmonary vasculature. Thus, any changes in these arteries yields a significant change in resistance to blood flow. The portion of the blood vessel responsible for the thickening of the pulmonary artery? The media layer of the blood vessel which contains the smooth muscle cells.

A hallmark of hypoxic PH is the thickening of the media, the section of the vasculature that comprises the pulmonary artery smooth muscle cells (PASMC’s). From in vivo studies, we know that in large hypoxic animals, there are subsets of undifferentiated resident smooth muscle cells with high proliferative potential in all branches of the pulmonary artery. In normal animals (normoxic animals), this does not occur; the resident smooth muscle cells are well-differentiated and have a low proliferative potential. Typically, at least in terms of hypoxia induced PH, it is the least differentiated cells that have the highest proliferative potential. This is a common observation. In humans with PAH, we observe the presence of these types of undifferentiated/proliferative cells. However, as an interesting side note, it has also been found that there are well-differentiated PASMC’s that appear to be hyperproliferative at baseline compared to PASMC’s from control patients. So markers of cell differentiation may not be a good marker of proliferative capacity of the PASMC.

PASMC’s are typically activated by the EC’s in the intima. Specifically, PASMC’s are activated by endothelin-1 (ET-1), the vasoconstrictive and pro-inflammatory mediator produced by EC’s (however, ET-1 can also be secreted by PASMC’s). Once activated, via the unfolded protein response, PASMC’s release pro-inflammatory and chemotactic mediators.

An interesting feature about resident PASMC’s is that once they are activated and release pro-inflammatory and pro-mitogenic factors, they can then create a feedback loop where those same cells respond to their own signals by increased proliferation/inflammation. One example of this is the HIF1/ET-1 axis: “…there is evidence that hypoxia induces PASMC ET-1 in a HIF1 dependent manner which induces a feed forward loop whereby ET-1 further stimulates HIF1-alpha protein and HIF1 gene expression.”¹

There is also evidence that recruited proinflammatory cells (perhaps via the outside-in method, coming in from the adventitia) can induce PASMC proliferation.

The Adventitia: Resident Fibroblasts and Immune Cells

And now to the adventitia… the key player in our “outside-in” hypothesis. The adventitia is the outermost layer of the blood vessel and acts as a supporting framework for the extracellular matrix. It contains conduits for nutrient supply and removal and for circulating cells (the vasa vasorum and lymphatic vessels). And, as we have discussed above, it may play a role in the initial steps of vascular inflammation and remodeling. The adventitia is home to resident macrophages, dendritic cells (DCs), progenitor cells, and fibroblasts (which have recently been found to be capable of exerting immune functions).

So how does the adventitia contribute to inflammation in the vasculature, specifically under hypoxia? Under hypoxic conditions, the vasa vasorum supplying the adventitia begins to expand and import recruited circulating immune and progenitor cells into the adventitia. The adventitia itself also begins to thicken due to extracellular matrix protein and collagen deposition. Furthermore, resident macrophages and fibroblasts become activated and proliferate. The adventitial fibroblast itself acts as a sentinel cell, being the first cell type to respond to vascular stresses (such as hypoxia and mechanical stress) by becoming activated. Once activated the adventitial fibroblast sentinel cell can upregulate contractile and ECM proteins, recruit inflammatory cells, and release compounds that affect PASMC tone and growth in the medial layer. At least in the context of hypoxia, where adventitial fibroblasts act as first responders, the inflammation really does originate completely from the “outside” (with the exception of the sensing of hypoxia, which likely occurs in the smooth muscle cells which act as “oxygen sensors”) and can progress inward, as opposed to being triggered by internal inflammatory states or vascular injuries.

Fibroblasts, macrophages, and dendritic cells (DC’s) present in the adventitia all posses machinery that, once activated, can potently respond to exogenous and endogenous danger signals. This machinery includes toll-like receptors (TLRs) and inflammasome components (NLRs). Once activated, each cell can release a variety of cytokines, chemokines, ROS and tissue remodeling proteins such as MMPS and TIMPS. In the setting of PH, there are increased numbers of these activated fibroblasts, macrophages, dendritic cells (DC’s) present in the pulmonary arteries.

Macrophages have a wide variety of functions due to their functional plasticity, and thus may be key in initiation, propagation, and resolution of immune responses: “macrophages can promote or resolve fibrosis, promote insulin resistance and obesity, are essential in thermoregulation through generation of catecholamines, are essential for wound healing, can promote and restrict T cell responses, promote angiogenesis, promote or suppress tumor growth, fight pathogens, and control homeostasis in local immune networks.” It is now evident that certain tissue resident macrophages like pleural macrophages are even able to renew and proliferate independently from the bone marrow. This means that the macrophages in the adventitia of the pulmonary arteries may be able to renew and proliferate on their own, being a primary source of perpetuating inflammation (local danger signals can trigger them to proliferate rapidly on the spot).

DC’s, on the other hand, encounter self and non-self (environmental) antigens at epithelial surfaces in the pulmonary vasculature, and coordinate innate and acquired immune responses. In PH, as well as other diseases like asthma and COPD, DC’s exhibit a preference for residing in the adventitia. Here, the DC’s may be able to modulate inflammatory and immunological processes.

Interestingly, it appears that macrophages and dendritic cells may be the “same cell” but operating on different locations of a functional continuum, i.e. macrophages are the result of state A, carrying out function A, while dendritic cells are the same cell in a different state B, carrying out function B: “…macrophages and DCs, based on the fact that no surface or functional marker definitively distinguishes macrophages from dendritic cells, do not represent separate entities but rather two extremes of regulated functional activation states on a continuum of a yet unknown number of functional activities. Chief among these are the capability of macrophages to mount strong proinflammatory cytokine responses (initiating innate immune responses) and DCs to be strong antigen presenters and inducers of T cell responses (initiating adaptive immune responses). However, as pointed out, both cell types can perform both functions in response to adequate stimulation.”

Activated adventitial fibroblasts also appear “to exert a functional plasticity reminiscent of that of macrophages/DCs in that they have been shown to express a combination of functional phenotypes including generation of proinflammatory cytokines and molecules necessary for antigen presentation and T-cell stimulation. This functional plasticity of the activated adventitial fibroblast may therefore play a key role in initiating and propagating adventitial inflammation through generation of numerous cytokines and chemokines that create a microenvironment tailored to fine-tuning the activation of tissue resident macrophages and DCs as well as promoting recruitment of blood derived inflammatory monocytes.”

It seems that, in general, a proinflammatory environment in the adventitia may be caused by the presence of antigens, in which case the dendritic cell may be the primary driver, or by hypoxia, vascular injury, or other causes (such as those that occur in hypoxia induced or idiopathic PH), in which case the macrophage would be the primary driver. However, a third cause may be due to epigenetic factors (caused by hypoxia, inflammation from autoimmune process, or other processes), which can lock immune cells into a specific state rendering them unable to respond to regulatory signals. This would then lead to a sustained pro-inflammatory phenotype in the adventitial fibroblast which would further sustain and lock macrophages and DCs into proinflammatory, pro-fibrotic, and pro-remodeling phenotype. Regardless of the cause, it is evident that “…an environment is created in chronically inflamed tissues, whereby the adventitia acts as a foster home for leukocytes leading to their inappropriate/pathologic retention and survival.”

More on Macrophages and Chronic Inflammation

So what about the persistence of inflammation in PH? Before we answer that, let’s briefly define the parenchyma and non-parenchyma. Parenchymal cells are cells that are part of the parenchyma, which is the functional part an organ. Non-parenchymal cells refer to cells that are part of the stroma, or the structural tissue (connective tissue) of an organ.

It appears that resident tissue macrophages may communicate with local lung (parenchymal) and connective tissue (non-parenchymal) cells to maintain homeostasis. Furthermore, the non-parenchymal cells could play a vital role in providing turn off signals to resident and recruited cells, such as resident tissue macrophages, resident fibroblasts, and recruited macrophages, which could thus promote resolution or inflammation: “…intricate cross-talk between resident and recruited macrophages with their [non-parenchymal connective tissue cells] is key in maintaining tissue homeostasis, coordinating an appropriate inflammatory response tailored to the inciting noxious agent and finally providing signals that allow for resolution when the inflammatory trigger has been removed. Malfunctioning of this cross-talk is thus hypothesized to result in aberrant permanent activation of macrophages and [non-parenchymal connective tissue cells] with subsequent progression to chronic non-resolving inflammation as the driver of pathologic tissue remodeling.”

There is evidence of this macrophage/connective tissue cell inflammatory crosstalk occurring in adipose tissue, as well as in conditions like cancer and rheumatoid arthritis. It is then plausible that this can also occur in PH.

Macrophages also have very plastic (i.e. “malleable”) phenotype. As part of their “duty”, they constantly survey the local tissue status and can change their phenotype based on the signals received from the local tissue microenvironment. Thus, an activated pro-inflammatory macrophage phenotype can transform into an anti-inflammatory pro-resolution phenotype if the appropriate local signals are present. This is important for therapeutic purposes because, if chronic non-resolving inflammatory processes are present, one could theoretically target the local tissue signals that are driving the macrophages to stay in a pro-inflammatory phenotype. For example, what if altering the metabolic microenvironment by metformin or AMPK activation, and other means, could help switch macrophages to anti-inflammatory phenotype?

The Role of Extracellular ATP and Nucleotides in Inflammation (and Support for Metabolic Therapies for Inflammation?)

Targeting the metabolic microenvironment could make sense seeing that extracellular ATP, other nucleotides (ADP, UTP, and UDP) and adenosine, all have been known to regulate vascular function, controlling blood flow, cell proliferation, migration, inflammation (ATP acts synergistically with cytokines and integrins), and chemotaxis. Purine homeostasis in particular is an important factor for proper vascular endothelial function.

It is known that the extracellular ATP in tumor microenvironments are 1000 times higher than normal. Extracellular nucleotides may even contribute to vascular diseases like PH. Extracellular ATP is released from adventitial fibroblasts, vasa vasorum endothelial cells, and inflammatory cells in response to hypoxia, inflammation, oxidative stress, and mechanical forces, all of which are experienced in PH. In addition, it is known that extracellular ATP induces a pro-inflammatory phenotype in immune cells like monocytes and macrophages by regulating cytokine and chemokine production.

Extracellular ATP is also released by adventitial fibroblasts and the vasa vasorum as a result of hypoxia or oxidative stress, which can thus act to activate macrophages. Stenmark et al. showed “that pulmonary artery adventitial fibroblasts and vasa vasorum endothelial cells (VVECs) are a potent source of extracellular ATP, which acts as an autocrine/paracrine factor augmenting hypoxia-induced VVEC angiogenesis.” In this case, metabolic dysregulation of the adventitia, leading to high extracellular ATP concentrations, could be a trigger for inflammatory processes in PH.

Adenosine, however, appears to be protective and anti-inflammatory. Extracellular adenosine inhibits the chemotactic response of immune cells to ATP, thus potentially preventing the excessive accumulation of inflammatory cells in the adventitia. It also prevents endothelial cell permeability via its receptor A1R. Animal model studies have indicated that A1R can attenuate endotoxin induced lung injury, pulmonary edema, and alveolar destruction. Studies have also shown “a significant attenuation of TNF-alpha induced VVEC permeability upon adenosine treatment, indicative of the barrier-protective effect of adenosine.” TNF-alpha is one of the most potent inflammatory mediators and regulates endothelial cell permeability, and its expression is increased under hypoxia, inflammation, and PH. Both macrophages and perivascular adipocytes are potent sources of TNF-alpha.

However, data indicate that A1R may be downregulated under conditions of chronic hypoxia, which may contribute to pulmonary vascular remodeling and inflammation. Stenmark et al. gives a great mechanistic explanation of the interplay of extracellular ATP and adenosine and how they are involved in pulmonary vascular remodeling under hypoxic conditions: “Endogenously released ATP, by acting on P2 purinergic receptors (P2R) results in angiogenic activation of the vasa vasorum, characterized by increased proliferation and dysregulated barrier properties. Elevated extracellular ATP is subsequently hydrolyzed by ectoenzymes… to adenosine. In turn, extracellular adenosine by acting on P1 purinergic receptors (P1R) induces a phenotypic switch of the vasa vasorum endothelial cell to a more quiescent state, characterized by low proliferation rate and improved barrier function. Inhibition of [ectoenzymes] by hypoxia and oxidative stress results in consistently elevated levels of extracellular ATP and lower levels of adenosine that eventually exacerbate pathological vascular remodeling.”

Aside from extracellular ATP, Stenmark et al. mention that “mediators produced downstream of glycolysis, which occurs in hypoxic PH and PAH, are able to directly affect pulmonary vascular remodeling.”

All of this evidence supports the idea that metabolic interventions could be implemented (e.g. in order to alter the status of extracellular ATP and adenosine, or glycolysis) to promote an anti-inflammatory and non-proliferative microenvironment.

The Role of ROS in Inflammation in PH

Reactive oxygen species (ROS) are increased in all forms of PH, and are thought to contribute to both vasoconstriction and vascular remodeling. ROS are produced by inflammation, and their production further activates inflammatory pathways. Thus, ROS act as a positive feedback loop for promoting inflammation once inflammation occurs. However, as with inflammation, it is not clear that all ROS are “bad”, especially in the context of PH (as we’ll describe soon). For example, ROS are necessary signals for repairing and building muscle during weight lifting. After you lift weights, you want ROS present to help rebuild and grow stronger.

The primary ROS in the vasculature are superoxide and hydrogen peroxide, the latter of which is involved in both physiological and pathophysiological cell signalling. Superoxide is degraded by the antioxidant enzyme superoxide dismutase (SOD) to yield oxygen and hydrogen peroxide. If there is not enough SOD present, superoxide reacts with local bioavailable nitric oxide (NO), thus reducing the local concentration of NO, and producing toxic peroxynitrite as a byproduct.

Hydrogen peroxide, on the other hand, is scavenged by antioxidant enzymes like glutathione peroxidase and catalase. Hydrogen peroxide, especially that generated by the mitochondria (mitochondrial ROS), is necessary for physiological cell signaling, but too much can be detrimental. Additionally, in the presence of iron, hydrogen peroxide decomposes into a toxic hydroxyl radical.

In the pulmonary vasculature, the primary sources of superoxide and hydrogen peroxide are NADPH oxidases (abundant in the adventitia), uncoupled eNOS, the mitochondrial electron transport chain (mitochondrial ROS), and xanthine oxidase. In diseased states, eNOS is uncoupled and produces superoxide. eNOS uncoupling can occur via: “deficiencies in L-arginine substrate; increased ADMA. an L-arginine analog; increased arginase activity; or BH4 deficiency due to low production or oxidation.”

Xanthine oxidase produces superoxide. “…XO-derived ROS contribute to injury in a number of processes associated with inflammation including ischemia-reperfusion injury, acute lung injury, COPD and cigarette exposure, and cancer.” XO also “promotes the inflammatory state of pulmonary mononuclear phagocytes through effects on HIF1alpha.”

Mitochondrial ROS, however, are controversial. Numerous studies implicate mitochondrial ROS and mitochondrial dysfunction in pulmonary vascular disease. However, mitochondria also act as oxygen sensors for the cell, producing mitochondrial ROS in the presence of oxygen which then goes to keep potassium channels open, and thus keep the vasculature in a vasodilated state. When oxygen levels decrease, so does mitochondrial ROS, and thus the potassium channels in the SMCs close causing vasoconstriction. In fawn hood rats that spontaneously develop PH, mitochondrial ROS is decreased. Also, under the setting of hypoxia, mitochondrial ROS is decreased. Thus it is not quite clear that hydrogen peroxide/mitochondrial ROS is either beneficial or detrimental. We know that it is necessary for vasodilation and proper cell signaling, but it can also initiate inflammatory pathways and cell damage.

The sum of all ROS produced in the lung microvasculature is likely higher than normal in PH however and probably causes net harm, since they are produced by inflammation, and go on to further promote inflammation. ROS produced by all of the above mentioned sources “can be activated by pro-inflammatory cytokines, including interleukins and tumor necrosis factor-alpha, and conversely, the ROS generated in the vessel wall can augment inflammation by activating redox sensitive targets including key transcription factors, NF-kB, AP-1, and HIF. In addition, ROS can modulate a wide range of other signaling molecules that impact inflammation, proliferation, migration, differentiation, and matrix production.”

Chronic Inflammation induces Epigenetic Changes

Evidence continues to emerge to support the idea that chronic inflammation leads to stable (and heritable) epigenetic changes in gene expression and cell function (leaving the underlying base DNA composition unchanged). There are three overall mechanisms of epigenetic regulation: 1) DNA methylation, 2) histone modifications, and 3) gene silencing (via microRNA’s).

A primary example of DNA methylation occurring in PH is that the SOD2 gene in the pulmonary arteries and plexiform lesions of PH patients is hypermethylated. When this hypermethylation is reversed, SOD2 is reduced. SOD2 is responsible for neutralizing the harmful superoxide radical.

Regarding HDAC’s, increased HDAC expression and activity is associated with increased vascular cell proliferation, and is known to contribute to the pathological remodeling of the pulmonary arteries in PH.

All of these epigenetic changes (methylation, HDAC activity, and microRNA activity) can occur in the setting of hypoxia and inflammation. Furthermore, HDAC’s in particular, once activated can regulate microRNA activity to create a feedback loop. This can explain the constitutively active phenotype of PH: “long term adaptation to chronic hypoxia involves significant modification of chromatin structure in order to maintain the hypoxic phenotype, even in the absence of HIF1.” Thus, chronic hypoxia is capable of inducing epigenetic changes in gene expression that are independent of the classical HIF pathway.

Concluding Remarks

Inflammation can either be a cause or consequence of PH. Regardless of this, inflammation operating via an “outside-in” mechanism, where infiltrating immune cells penetrate inward into the blood vessel, helps to contribute to a perpetual increase in pulmonary vascular dysfunction and remodeling, leading to the pathological development of PH. Emerging evidence indicates a growing role for the adventitia and resident immune cells in the adventitia in the inflammatory processes that lead to PH, and it appears that the adventitia is a perfect microenvironment for hosting and promoting pathological inflammatory responses. If sustained for long enough, chronic inflammation can induce epigenetic changes that further lock-in this inflammatory state.

Extracellular ATP, nucleotides, ROS, macrophages, and adventitial fibroblasts all are mediators in the inflammatory processes mentioned above, and thus could be therapeutic targets. Furthermore, since it is plausible that autoimmunity and metabolic dysfunction contribute to inflammation, therapeutically targeting these areas may also help resolve inflammation and PH. Metabolic therapies can take the form of a drug like metformin, or even an anti-inflammatory diet (removing foods that trigger allergic reactions or autoimmune responses, e.g. removing wheat for celiac disease) like Paleo or AIP, or a combination of those. I’m obsessed with diet and metabolism, and strongly believe that what you put in your body can either greatly help you or harm you. Your stomach is after all one of the only areas where the outside world comes in contact with the “inside” world. As such, it harnesses the largest concentration of immune cells in your body. Foods that induce gut permeability can thus potentially create autoimmune responses. So, in the end, food could be a great therapy, in combination with modern medicine for resolving inflammation, and could maybe even help to reverse PH.

Resources/References:

Dave Berry

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