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STAT6 Protein May Have Role In PH Tied To Sleep Apnea, Study Finds
Activation of an immune signaling molecule called STAT6 may lead to pulmonary hypertension (PH) in people with oxygen deprivation due to obstructive sleep apnea, according to a recent study in mice.
Obstructive sleep apnea is a common sleep disorder characterized by chronic intermittent hypoxia, or repeated episodes of stopping and starting to breathe while asleep.
In the study, STAT6 levels were elevated in the lungs of a mouse model of intermittent hypoxia-induced PH. Deleting the protein eased disease severity in the mice and reduced signaling of an immune pathway called the Th2 response that's seen to be a driver of PH.
"These findings exhibit the critical role of STAT6 in the pathogenesis [development] of CIH [chronic intermittent hypoxia] induced PH by regulating Th2 immune response," the researchers wrote. "STAT6 could be a significant therapeutic target for [obstructive sleep apnea-related] PH," they added.
Obstructive sleep apnea is known to raise the risk of pulmonary hypertensionThe study, "STAT6 deficiency mitigates the severity of pulmonary arterial hypertension caused by chronic intermittent hypoxia by suppressing Th2-inducing cytokines," was published in Respiratory Research.
Breathing starts and stops repeatedly during sleep with obstructive sleep apnea due to a blockage or narrowing in the airways, leading to chronic intermittent hypoxia.
The sleep disorder raises a risk of PH, elevated pressure in the blood vessels of the lungs (the pulmonary arteries), and other cardiovascular problems.
Factors underlying how PH arises in people with this disorder are not completely understood, but inflammation is believed to play a role. Research has shown that low oxygen conditions create an inflammatory environment capable of driving vascular remodeling, a series of structural changes in the pulmonary arteries that contribute to PH, the study noted.
One possible key player is STAT6, a protein involved in lung inflammatory responses. STAT6 is involved in the activation of the Th2 immune response, which is implicated in PH development and progression. It also has been found to be elevated in people with obstructive sleep apnea and animal models of chronic intermittent hypoxia.
Scientists in China explored the potential role of STAT6 and Th2 responses in driving intermittent hypoxia-induced PH.
PH, vascular remodeling less severe in mice lacking STAT6 proteinThey found phosphorylated STAT6 — an activated form of the protein — at higher levels in lung tissue of a mouse model of hypoxia-induced PH relative to tissue from the lungs of healthy mice, along with signs of an increased Th2 immune response.
When the mice were genetically engineered to lack STAT6, PH severity and signs of vascular remodeling fell. The Th2 immune response was suppressed, including reductions in Th2 immune cell populations and related signaling molecules, namely IL-13 and IL-4.
Further experiments in cultured pulmonary artery cells showed the excessive cell growth characteristic of vascular remodeling in PH appeared to be driven by IL-4; specifically, the signaling molecule showed an ability to activate STAT6.
"In summary, our study demonstrates that IL-4/STAT6 participates in CIH-induced PH by regulating Th2 immune responses," the researchers wrote, noting that its findings help to position STAT6 as a therapeutic target for PH associated with chronic intermittent hypoxia.
They noted, however, that a number of molecules other than IL-4 can lead to STAT6 activation and may play a role in the process.
"Further validation of these factors' effects on STAT6 in the CIH model is required," the researchers wrote.
Future studies aiming to confirm STAT6's role in sleep apnea-induced PH would need to look at the protein's levels in lung tissue from patients, as animal models do not fully replicate the features of human disease, they added.
STAT6, New Therapeutic Target For Obstructive Sleep Apnea-related Pulmonary Hypertension
Respiratory
One potentially serious complication of obstructive sleep apnea (OSA) is pulmonary hypertension (PH). Based on previous research that revealed involvement of perivascular immune and inflammatory responses in regulation of vascular remodeling and PH processing, researchers from Fudan University investigated the immunologic factors linked to OSA-induced PH.
BioWorld Science Cardiovascular Inflammatory RespiratoryObstructive Sleep Apnea
Obstructive sleep apnea is caused by the collapse of the upper airway during sleep. The muscles supporting soft tissues in the throat relax, narrowing or closing the airway and temporarily interrupting breathing.
Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder.
Normally, air should flow smoothly from the mouth and nose into the lungs at all times, including during sleep.
Periods when breathing stops completely are called apnea or apneic episodes. In OSA, the normal flow of air is repeatedly stopped throughout the night. Events when breathing is partially obstructed are called hyponeas. In order for breathing to resume, the brain arouses.
Snoring is often associated with OSA, especially if the snoring is interrupted by periods of silence. Snoring is caused by airflow squeezing through the narrowed airway space.
It's important to remember that snoring doesn't necessarily indicate something potentially serious, and not everyone who snores has OSA.
People with OSA often report experiencing daytime sleepiness. In addition to having to arouse in order to restablish breathing, OSA causes episodes of decreased oxygen supply to the brain and other parts of the body, so sleep quality is poor. This causes daytime drowsiness and a lack of clarity in the morning.
Those who share beds with people with OSA may report the following about their partner:
These symptoms are also often detected when checking on another complaint or during health maintenance screening.
People with OSA may also experience the following symptoms:
Daytime drowsiness puts people with sleep apnea at risk for motor vehicle crashes and industrial accidents. Treatment can help to completely relieve daytime drowsiness.
The following are some conditions associated with OSA:
The risk for OSA increases if you have physical features that narrow your upper airway. Risk factors of OSA include:
Untreated OSA can cause serious health problems, such as:
Proper diagnosis and treatment are essential for preventing complications.
People who suspect they may have OSA might go directly to their doctor, or some may use a wearable to screen for the condition.
An accurate diagnosis of sleep apnea begins with a complete history and physical examination. A history of daytime sleepiness and snoring are important clues.
Your doctor will examine your head and neck to identify any physical factors that are associated with sleep apnea.
They may ask you questions about daytime drowsiness, sleep habits, and quality of sleep.
The following tests may be performed to diagnose OSA.
Polysomnography (PSG)
During a polysomnography, you sleep overnight in a hospital or sleep center while connected to a variety of monitoring devices that record physiologic data.
Patterns of abnormalities during sleep may indicate sleep-disordered breathing as well as many other sleep disorders.
While you sleep, the devices will measure the activity of different organ systems associated with sleep. It may include:
EEG and EOM
During an EEG, electrodes are attached to your scalp that will monitor brain waves before, during, and after sleep. The EOM records eye movement.
A small electrode is placed 1 centimeter above the outer upper corner of your right eye, and another is placed 1 centimeter below the outer lower corner of your left eye. When your eyes move away from the center, this movement is recorded.
Brain waves and eye movements tell doctors about the timing of the different phases of sleep. The two broad phases of sleep are non-REM (non-rapid eye movement) and REM (rapid eye movement).
Decreased muscle tone and paralysis occur during REM sleep.
EMG
To record the EMG, electrodes are placed on your chin: one above your jawline and the other below it. Other electrodes are placed on each shin.
The EMG electrodes pick up the electrical activity generated during muscle movements. Muscle relaxation should occur during sleep. The EMG picks up when your muscles relax and move while you're sleeping.
ECG
A single lead ECG records the electrical signals from your heart during the sleep study to monitor your heart rate and rhythm.
Pulse oximetry
In this test, a device called a pulse oximeter is clipped onto a thin area of your body that has good blood flow, such as a fingertip or earlobe.
The pulse oximeter uses a tiny emitter with red and infrared LEDs to measure the oxygen saturation level of your blood. This level may decrease during episodes of apnea.
The goal for the treatment of OSA is to make sure airflow isn't obstructed during sleep. Treatment methods include the following:
Weight loss
Weight management and exercise are usually recommended for people with OSA who also have obesity. The newer drugs used to treat obesity may play an increasingly important role in treatment of OSA.
Although it may not lead to complete remission, weight loss has been linked with a decrease the severity of OSA.
Losing weight, if your doctor has recommended it, could also reduce blood pressure, improve your quality of life, and decrease daytime sleepiness.
Continuous positive airway pressure (CPAP)
The face mask gently delivers positive airflow to keep the airways open at night. The positive airflow props the airways open.
CPAP is a highly effective treatment for OSA.
For people with mild or moderate OSA who don't benefit from CPAP therapy, an oral appliance is a reasonable alternative to positive airway pressure.
Bilevel positive airway pressure (BPAP)
BPAP machines, sometimes called BiPAP machines, have settings that deliver two pressures in response to your breathing: inhaled pressure and exhaled pressure. This means the pressure changes during inhaling versus exhaling.
Sleeping on your side
Since sleeping on your back (supine position) can make OSA worse for some people, positional therapy is used to help you learn to sleep on your side.
Surgery
There is no consensus regarding the role of surgery in adults with OSA. In general, you may consider surgery when CPAP or BPAP machines or an oral appliance aren't effective.
Surgical treatment may be the most effective for people who have OSA due to a severe, correctable, obstruction of the upper airway.
Being a surgical candidate depends on factors like:
Surgical evaluation begins with a physical exam to check on the anatomy of your upper airway.
Your doctor will insert a flexible laryngoscopy, a thin instrument inserted through your nose that lights and magnifies the upper airway, while you are awake or, if necessary, asleep.
Surgical treatment for OSA provides long-term benefits in some people, although the complete elimination of OSA is often not achieved, depending on the specific procedure. For example, electrical stimulation of some of the nerves going to tongue muscles may be effective.
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