Levels of Cytokines Differ Between Sexes With PAH, Study Suggests

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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The levels of blood-circulating inflammatory molecules differ between men and women with pulmonary arterial hypertension (PAH) and correlate with disease severity, a study suggests.

Notably, the levels of two proteins — called IL-6 and MIP-1alpha — were predictors of poorer survival statistics.

These findings suggest that patient stratification may help assess those better suited for anti-inflammatory therapies, the investigators said.

The study, “Cytokine profiling in pulmonary arterial hypertension: the role of redox homeostasis and sex,” was published in the journal Translational Research.

PAH is a rare type of pulmonary hypertension characterized by the narrowing of the pulmonary arteries that carry blood from the right ventricle of the heart to the lungs.

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While the exact mechanisms leading to PAH are not fully understood, inflammation and immune responses are believed to drive disease development by triggering the release of cytokines — molecules that mediate and regulate immune and inflammatory responses.

Cytokines lead to blood vessel remodeling that contributes to the progressive narrowing of the small pulmonary arteries and increase in pulmonary blood pressure.

The type of immune response, however, may vary with sex. Preclinical studies with PAH rat models suggested that males are more likely to develop inflammatory and scarring responses while females lacked an inflammatory response, though their cells tended to grow and divide more. Also, males exhibited more progressive PAH.

However, whether inflammation in patients with PAH also varies in a sex-specific manner is unknown.

To answer this, a team led by researchers at the University of Arizona College of Medicine analyzed the levels of blood cytokines in 140 PAH patients (41 men and 99 women) and 50 healthy participants (29 men and 21 women), who served as controls.

Idiopathic (no known cause) PAH was the most common type of PAH, seen in 56.1% of men and and 42.4% of women. About 30% of the PAH patients had never been treated, about 30% received monotherapy, and another about 30% double therapy. The remaining about 10% received triple therapy.

Inflammation is closely related with oxidative stress, which occurs when damaging reactive oxygen species (ROS), also called free radicals, outweigh the body’s antioxidant defenses.

The researchers then measured the oxidation-reduction potential (ORP) and assessed how cytokine production related with oxidative status.

They then assessed the inflammatory response by measuring the levels of the 27 cytokines in PAH patients (irrespective of their oxidation status). Several cytokines were elevated in both men and women with PAH relative to healthy subjects.

Two molecules, called eotaxin and basic fibroblast growth factor (FGFb), were elevated in women only.

When analyzing cytokine levels relative to patients’ ORP profile, the researchers found that interleukin 1 beta (IL-1beta) was elevated in participants with a higher ORP.

Other molecules — IL-1ra, IL-10, eotaxin, interferon (INF)-gamma, MCP-1, MIP-1alpha, and vascular endothelial growth factor — were increased in samples from both men and women with PAH and a low ORP.

A smaller fraction, however, varied with the ORP status in a sex-specific manner. Levels of IL-2, IL-7, IL-13, and IL-17 were increased in the samples with the highest ORP specifically in women. In contrast, the levels of IL-5, IL-6, IL-15, and G-CSF were increased specifically in men with a low ORP.

The researchers then assessed whether oxidative status and sex correlated with disease parameters.

Their analysis showed that in men the elevated levels of six cytokines (IL-8, MIP-1alpha, FGF basic, IFN-gamma, IP10, MIP-1beta) correlated with increased PAH severity. In women, only three cytokines (IL-1b, IL-9, and IP10) correlated with higher PAH severity. In fact, most cytokines correlated with lower PAH severity, “suggesting that not an elevated production of these cytokines, but rather their decrease corresponds to more severe disease,” the team wrote.

“We conclude that in females, cytokines may simultaneously play a role in the PAH progression and the adaptive responses,” they added.

Only three of 21 cytokines significantly correlated with the disease parameters in both men and women. FGFb and INF-gamma had a positive correlation with PAH severity in men only (meaning their greater levels associated with reduced disease severity), while the opposite was seen in women.

This suggests that “sex-specific inflammatory profiles differentially contribute to PAH severity,” the researchers wrote.

They then applied machine learning algorithms that were trained on the combination of cytokine and ORP profiles as a way to predict mortality.

Results showed that the algorithm was able to predict PAH mortality with an accuracy of 80%.

Levels of five cytokines — IL-6, MIP-1alpha, IL-7, IL- 9, and tumour necrosis factor (TNF)-alpha — were significantly different comparing survivors and nonsurvivors. IL-6 and MIP-1alpha were increased in patients who died, while the remaining cytokines were decreased.

Further analysis showed that levels of IL-6 and MIP-1alpha above a certain threshold — 3.05 picograms per millilitre (pg/ml) and 1.74 pg/ml, respectively — correlated significantly with lower chances of survival.

Overall, these findings show that “the profile of circulating cytokines in PAH patients is redox- and sex-dependent, suggesting the vital need to stratify the patient cohort [group] subjected to anti-inflammatory therapies,” the researchers wrote.

“Combined cytokine/redox profiling showed promising value for predicting the patients’ survival,” they concluded.