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...
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...
20Oct/16

“Matrix metalloproteinases and their inhibitors in pulmonary hypertension” – A Review

This past week, I delved into the arena of Matrix Metalloproteinases and their role in disease and Pulmonary Hypertension. One of the first papers that I read with regards to this is by S.S. Pullamsetti et al. entitled “Matrix metalloproteinases and their inhibitors in pulmonary hypertension”. My review and summary of this paper is below. Abbreviations: ECs = Endothelial Cells SMCs = Smooth Muscle Cells ECM = Extracellular Matrix PAH = Pulmonary Arterial Hypertension MMPs = Matrix Metalloproteinases TIMPs = Tissue Inhibitors of Matrix Metalloproteinases In PAH, complex remodeling is observed in the pulmonary vasculature that involves all components of the blood vessel.… Read More...
22Sep/16

Lectins, Tissue Transglutaminase, & PH

As per this talk by Robb Wolf at UCSF (at ~1 hour in), non-Western Huntington’s disease carriers don’t seem to express the disease. Since Huntington’s Disease is a rare genetic neurodegenerative disease, this is intriguing and suggests that the expression of the disease may be epigenetic. As he points out a few minutes later, tissue transglutaminase has been implicated in Huntington’s Disease. What does this have to do with epigenetics and PH? Tissue transglutaminase is an enzyme that is responsible for modifying most of the body’s proteins. A key tenant of the “Paleo Diet” and similar metabolic/nutritional therapies is that consumption of dietary lectins found in grains and legumes play a role in the development of a variety of diseases by escaping into the bloodstream from the gut and triggering immune responses as well as interacting with the enzyme tissue transglutaminase.… Read More...
06Sep/16

“Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung” – A Review

This is a review and summary of a recent paper entitled “Metabolic Changes Precede the Development of Pulmonary Hypertension in the Monocrotaline Exposed Rat Lung”. In this study, metabolomic profiling was used in an animal model of PH to try to identify biomarkers of early stage PH, in hopes of identifying a process to diagnose PH earlier. At the end of this post, I’ve included a chart summarizing all of the biomarkers found in the study. Some terms: MCT = Monocrotaline SMC = Smooth Muscle Cell EC = Endothelial Cell Summary & Key Findings In the MCT animal model, they observed metabolic changes in “multiple pathways associated with the development of PH, including activated glycolysis, increased markers of proliferation, disruptions in carnitine homeostasis, increased inflammatory and fibrosis biomarkers, and a reduction in glutathione biosynthesis.” While less pronounced, the metabolic data derived from this study compared favorably with prior work carried out in humans with PH: “In support of our data in the MCT-exposed rat, PH patient metabolomic data also observed a significant elevation of glucose and fructose 6-phosphate levels [7].… Read More...