All posts by Dave

05Sep/17

Reactive Oxygen and Nitrogen Species in Pulmonary Hypertension

  In pulmonary hypertension, there is pathological remodeling of the blood vessels due to a pathological hypertensive environment within the vasculature. This hypertensive environment influences how all cells of the vasculature (endothelial cells and smooth muscle cells), as well as fibroblasts and immune cells behave. The environment typically activates fibroblasts and immune cells, causes de-differentiation in smooth muscle cells, induces the contractile phenotype in smooth muscle cells, and may even pushes endothelial cells to failure. How this pathological hypertensive environment occurs is unknown. For example, it could arise from underlying inflammation, from hypoxia, or an apoptosis process gone haywire… There are many theories.… Read More...
10Aug/17

Antioxidants and Reactive Oxygen Species in PH – Do Antioxidants Help or Hurt PH?

While it may not be the cause, evidence from several studies that supports the fact that increased oxidative stress and reactive oxygen species (ROS) together with decreased antioxidant activity can contribute to enhanced pulmonary vasoconstriction, vascular remodeling, and right heart dysfunction in pulmonary hypertension. Despite this evidence however, it is still unknown whether or not an oxidant/antioxidant imbalance contributes directly to the development of severe PAH. Answering this question is the aim of the recent paper reviewed in today’s post by Jernigan et al., “Contribution of reactive oxygen species to the pathogenesis of pulmonary arterial hypertension”. ROS in PH Many studies have shown that there is an imbalance of oxidant production and antioxidant capacity in the pulmonary vasculature of PH patients.… Read More...
08Aug/17

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.… Read More...
12Mar/17

The Cholesterol Paradox, Part 3 – LDL in Heart Disease & Pulmonary Hypertension

There is more to LDL than meets the eye… While it is true that LDL is an established marker of cardiovascular disease risk, we need to be clear just how and why exactly this is so. First things first. LDL is a means for delivering cholesterol to tissues that need it (and all cells need cholesterol to survive). Cholesterol (and thus LDL) is necessary for life: it is involved in hormone synthesis (including sex hormones), cell wall synthesis and maintenance, and the synthesis of vitamin D and bile acids. Additionally, it is involved in the process of repairing cellular injury. Now to tackle a few myths… Myth #1 – LDL is the cause of Heart Disease While LDL is involved in the atherosclerosis process, it isn’t the driving force, the immune system is… Atherosclerosis is the result of an immune response, by definition you need a macrophage deposited in an arterial wall to initiate the process of atherosclerosis.… Read More...
10Feb/17

The Cholesterol Paradox, Part 2

This is part of a series of posts where I share and dissect information about cholesterol, the science behind cholesterol, and common fallacies surrounding cholesterol. Most of these posts are going to be short… where I just share bits of information that I’ve archived or that I’ve recently found, and some thoughts surrounding them. For Part I of this series, click here. For this post, I want to reflect on a quote from Metabolic Regulation: A Human Perspective by Keith N. Frayn (my emphasis added): “Perhaps surprisingly, the amount of cholesterol in the diet is not a major factor affecting the blood cholesterol concentration.… Read More...
26Jan/17

Can Diet Help Improve Pulmonary Hypertension? An Insight from Inflammatory Bowel Disease Research

While reading a recent paper entitled “Endothelial dysfunction in inflammatory bowel diseases: Pathogenesis, assessment and implications” I experienced a feeling a remarkable familiarity… I felt as if I was reading a paper about endothelial dysfunction in Pulmonary Hypertension. It appears that endothelial cell (EC) dysfunction in both inflammatory bowel disease (IBD) and pulmonary hypertension (PH) are quite similar: the same mechanisms of dysfunction abound, the same proinflammatory molecules are released. There is proliferation, smooth muscle cell tone activation, platelet aggregation, hypoxia, eNOS downregulation, imbalance between vasodilators and vasoconstrictors, etc.  Even though this kind of makes sense (that pathology in a cell such as an endothelial cell could be quite similar regardless of what tissue/organ it occurs in), it nevertheless is quite interesting.… Read More...
12Jan/17

“Aldehyde dehydrogenase 2 protects against oxidative stress associated with pulmonary arterial hypertension” – A Review of Lipid Peroxidation in PH

A key underpinning in the pathological development of PAH is thought to be the abnormal proliferation of pulmonary arterial smooth muscle cells (PASMCs), and it is well known that oxidative stress plays a key role in this process. One oxidative stress pathway is lipid peroxidation, which has been found to contribute to abnormal PASMC growth. A major end product of lipid peroxidation processes, specifically from omega-6 peroxidation, is the compound 4-hydroxynonenal (HNE). [For those of a chemistry bent, 4-HNE is an aldehyde]. Of interest is the fact that 4-HNE has been found to contribute to PASMC growth and this compound has also been found in excess in the pulmonary arteries of PH patients.… Read More...
31Dec/16

Pulmonary Edema in PH & PVOD – Potential Causes of PVOD Misdiagnosis

*DISCLAIMER: These are my own thoughts and opinions based on my research and are not meant to be taken as medical advice.* Below is a potential explanation for how edema could occur in Pulmonary Hypertension (PH) patients receiving vasodilator therapy, thus leading to them being potentially misdiagnosed for Pulmonary Veno-Occlusive Disease (PVOD)… It makes sense to think that because a PH patient does not respond to vasodilator therapy well, or experiences edema due to vasodilator therapy, it may be an indication that they have PVOD. The theory goes that vasodilators can “open” up the vasculature (even in PH patients) and if the veins are “occluded” or non-responsive/rigid, then there is a large pressure difference that occurs when the blood flows from the “open” to “closed/rigid” section causing backpressure and edema: “PAH-specific vasodilator therapies may cause an augmentation of pulmonary arteriolar blood flow against the fixed resistance of occluded pulmonary venules and veins.… Read More...
28Oct/16

Appearances Can Be Deceiving – The Problem With Genetic Knockout Mice Studies

Appearances Can Be Deceiving – The Problem With Genetic Knockout Mice Studies When scientists want to study the effect that a gene has on an organism, they perform what is called a “knockout” experiment. The knockout method is an experimental method, usually employed in mice, whereby the expression of a specific gene under study is blocked. The goal of this method is to learn about what effect the absence of the gene has on the animal. Due to the inevitable rise in the importance of genetic targeting in therapeutics, the knockout model has become a very important staple in studying the functions and endogenous expression patterns of single genes in vivo.… Read More...
26Oct/16

“A proteomic approach to altered innate and adaptive immunity in the pathogenesis of PAH” – A Synopsis

Below is a synopsis of “A proteomic approach to altered innate and adaptive immunity in the pathogenesis of PAH”, a talk by Marlene Rabinovitch (MD, Stanford) given at the Vera Moulton Wall Center for Pulmonary Vascular Disease (video below). It is one of my favorite talks so far in this series of lectures… Hypothesis: there is an abnormal immune response (both innate and adaptive) affecting pulmonary arteries that is common in all forms of PAH Altered adaptive immunity in PAH pathogenesis What if antigens produced in lung are the site for autoantibody formation and immune complex deposition directly in the lung and in the perivascular area?… Read More...