Understanding Emphysema – The Role of HIF-2α

by Adrienne Mueller, PhD
August 4, 2020

Pulmonary diseases like emphysema are the third leading cause of death in the US and the fourth leading cause worldwide. Emphysema occurs when air sacs in the lungs are damaged; such as after exposure to smoke, air pollution, or chemical fumes and dust. As emphysema gets worse, the walls of the air sacs weaken and rupture, creating larger air spaces inside the lungs. Having larger air spaces means the lungs have less opportunity to take up oxygen and therefore less oxygen enters the blood stream. The damaged air sacs also make it harder for the lungs to cycle out old, oxygen-depleted air for new, oxygen-rich air. Despite emphysema’s broad prevalence and severe outcomes, current treatment methods target symptom relief – not prevention or reversal of the disease itself.

Smoke inhalation, one of the primary causes of emphysema, has been shown to cause a decrease in the expression of a particular protein that is enriched in the lungs: HIF-2α. HIF proteins are known to be involved in oxygen processing both in low-oxygen environments, where they trigger the expression of genes that improve oxygen uptake efficiency, as well as in normal oxygen environments, where they help maintain air sac architecture and promote cell survival. Given the facts that 1) smoke inhalation triggers a decrease in HIF-2α, and 2) HIF-2α has a known important role in oxygen processing and maintaining lung air sac architecture, a group of scientists including first author Shravani Pasupneti, MD, senior authors, Xinguo Jiang, MD, PHD and Mark Nicolls, MD of Stanford University and Nobel-Laureate Gregg Semenza, MD, PhD of Johns Hopkins, chose to investigate whether changes in HIF-2α levels could be directly responsible for emphysema.

In their study, recently published in the American Journal of Respiratory and Critical Care Medicine, the authors used genetic manipulations to both decrease and increase HIF-2α levels. When they decreased HIF-2α levels in mice, they were able to recreate the lung pathology of emphysema (e.g. air sac enlargement). They also showed that this effect was specific to HIF-2α, because decreasing levels of a similar protein, HIF1α, did not cause lung-related dysfunction. Not only did they show that lack of HIF-2α causes emphysema, but they also demonstrated that the presence of HIF-2α is actually protective. Increasing levels of HIF-2α in mice prevented the animals from the pathological air sac enlargement and cell death that is typical in emphysema. Combined, Pasupneti et al’s results show that loss of HIF-2α function could be directly responsible for the symptoms seen in individuals with emphysema. Identifying ways to preserve HIF-2α function is therefore a promising opportunity for therapies that would limit emphysema progression – or even prevent emphysema in at-risk patients.

An editorial of this study by Emma Hodson MD, PHD and 2019 Nobel-laureate Peter Ratcliffe, MD was published alongside this manuscript and provides further context for the authors’ results.

Other Stanford Cardiovascular Institute-affiliated authors include Wen Tian, Allen B. Tu, Petra Dahms, Eric Granucci, Menglan Xiang, and Eugene Butcher.

Dr. Shravani Pasupneti

Dr. Xinguo Jiang

Dr. Mark Nicolls