Targeting inflammation in sickle cell disease with fatty acids

sickle cell disease red blood cells
(OpenStax College/Wikimedia Commons)

Painful, tissue-damaging vaso-occlusive crises (a.k.a. pain crises) are one of the key clinical concerns in sickle cell disease (SCD). The characteristic C-shaped red blood cells of SCD become jammed in capillaries, starving tissues of oxygen and triggering searing pain. Over a patient’s life, these repeated rounds of oxygen deprivation (ischemia) can take a heavy toll on multiple organs.

There’s some debate as to why these crises take place—is the sickled cell’s shape and rigidity at fault, or are the blood vessels chronically inflamed and more prone to blockage? Either way, doctors can currently do little to treat vaso-occlusive crises, and nothing to prevent them.

The inflammation view, however, is leading some researchers to ask whether omega-3 fatty acids—which can alleviate inflammation—might be part of the solution. A recent mouse study in the journal Haematologica, led by Mark Puder, MD, PhD, of Boston Children’s Vascular Biology Program, and Carlo Brugnara, MD, of the hospital’s Department of Laboratory Medicine reveals some molecular clues and suggests that human trials of omega-3s might be a good next step.

One of these fats is not like the other

Dietary fatty acids fall into different families based on their molecular structure, and those differences impact the acids’ effects in the body. Omega-6 fatty acids—which factor heavily in the Western diet—push the immune system into a pro-inflammatory state. Omega-3s tend to be anti-inflammatory.

Some clinical studies have looked at omega-3 supplementation in people with SCD, while other studies have looked at the effect of omega-3s on vascular damage from inflammation and ischemia. But none have defined the connections at the molecular/mechanistic level between omega-3 action and the inflammatory biology of SCD.

To explore this link, Puder, Brugnara and colleagues in Italy fed groups of healthy mice and mice with SCD two test diets—one rich in fish oil (high in omega-3s) and one rich in soy (lots of omega-6s)—for six weeks. They then looked for any effects of the diets on red blood cell (RBC) structure, inflammatory markers and other physiologic features.

omega-3 omega-6 fatty acids sickle cell disease
Generic structures of omega-3 (top) and omega-6 (bottom) fatty acids. (Edgar181/Wikimedia Commons)

Remaking cell membranes

Each experiment highlighted beneficial effects of omega-3s in the SCD mouse model. Take RBC structure. In SCD, the fatty-acid-rich lipid membranes of RBCs are much higher in omega-6 concentration than normal, and have much higher omega-6/omega-3 composition ratios.

“Sickle cell disease is a disease of hemoglobin, but its manifestations are those of a membrane disease,” says Brugnara, who has conducted landmark research on SCD for more than 20 years. “Which is why the field is now curious about whether we can reduce symptoms and improve perfusion of tissues by manipulating cell membranes.”

The research team found that the RBC membranes of both normal and SCD mice fed the fish diet were significantly higher in omega-3s and had much lower omega-6/omega-3 ratios. In addition, RBCs from the fish-fed SCD mice were larger and had lower concentrations of hemoglobin than those of their soy-fed counterparts. And that might be a good thing.

“In SCD, because of membrane damage, the red blood cells tend to dehydrate,” explains SCD specialist Matthew Heeney, MD, clinical director of the Blood Disorders Center at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, who was not involved in the study. This increases the cells’ hemoglobin concentration, and “makes the cells more prone to sickling and clogging.”

SCD mice on the fish diet also had fewer cellular and molecular signs of:

  • inflammation
  • vascular activation (the membranes of “activated” endothelial cells within blood vessels are “sticky,” and more prone to snaring sickled RBCs) and
  • ischemic damage in their arteries, lungs and livers

than those fed the soy diet.

“In our model, this dietary intervention modifies a lot of things related to vascular damage and inflammation,” says Brugnara. “It takes us in a slightly different direction: modifying the SCD environment rather than the hemoglobin defect itself.”

A future for combination treatments?

If you have sickle cell disease, don’t take these results as license to start taking fish oil supplements just yet. It’s not yet known whether omega-3s can affect inflammation markers in people as they did in mice.

“This is an interesting proof of concept,” says Heeney. “As doctors we tend to have a blind spot when it comes to nutritional impacts in sickle cell. There may be benefits, but we have to do the science.”

The mouse data do give an idea of the mechanisms by which omega-3s might work in SCD. They also suggest that omega-3s could one day be part of a combined approach that targets several aspects of SCD at once.

“We have hydroxyurea, which boosts fetal hemoglobin production, improves anemia and reduces clinical symptoms,” says Brugnara. “It would be wonderful to combine this with treatments that block adhesion between RBCs and blood vessel walls along with ones that change the RBC membranes’ lipid makeup.”