Shravani Pasupneti, MD, on Endothelial HIF-2α for Preventing Emphysema
In this podcast, Shravani Pasupneti, MD, talks about her team's latest study, which aimed to evaluate the role of endothelial-cell HIF-2α in the pathogenesis of emphysema in mice.
- Pasupneti S, Tian W, Tu AB, et al. Endothelial HIF-2α as key endogenous mediator preventing emphysema. Am J Respir Crit Care Med. 2020;202(7):983-995. https://doi.org/10.1164/rccm.202001-0078oc
Shravani Pasupneti, MD, is an instructor of medicine in the Division of Medicine, Department of Pulmonary, Allergy, and Critical Care, at Stanford University in Stanford, California.
Amanda Balbi: Hello everyone, and welcome to another installment of Podcasts360—your go-to resource for medical news and clinical updates. I’m your moderator, Amanda Balbi with Consultant360 Specialty Network.
Endothelial injury may provoke emphysema, but molecular pathways of disease development require further discernment. Emphysematous lungs exhibit decreased expression of hypoxia-inducible factor-2α (or HIF-2α)-regulated genes, and tobacco smoke decreases pulmonary HIF-2α concentrations.
A new study aimed to evaluate the role of endothelial-cell HIF-2α in the pathogenesis of emphysema in mice. My guest today is the lead author of that study, Dr Shravani Pasupneti, who is an instructor of medicine in the Division of Medicine, Department of Pulmonary, Allergy, and Critical Care, at Stanford University in Stanford, California.
Thank you for joining me today, Dr Pasupneti. To start, can you tell us why your objective was important to study?
Shravani Pasupneti: Emphysema is a really prevalent disease, but unfortunately the therapies that exist only alleviate symptoms and don't prevent or reverse the disease. But there's been a few lines of evidence that have come out recently, suggesting that the hypoxia-inducible factors (or HIFs) can be relevant to COPD.
To the first of these was a study of patient with COPD, where the investigators found that of all of the genes that they looked for, only expression of HIF-regulated genes correlated with COPD severity. Put another way, lower expression of HIF-related genes was associated with more severe emphysema.
The second is that there's really a well-accepted idea that COPD involves a reduction in pulmonary vascular blood flow, an increase in epithelial cell death. So, this in combination with one of our previous findings, where we showed that HIF-2 is necessary to maintain large very micro vasculature and then other people who have shown that tobacco smoke decreases HIF-2 expression in the lungs and that endothelial cells are among the highest source of HIF-2 the lungs, led us to hypothesize that HIF-2 may actually be relevant in the pathogenesis of emphysema.
Amanda Balbi: You and your colleagues evaluated the lungs of mice after they were exposed to SU5416—a VEGFR2 inhibitor—in order to induce emphysema. Then you compared those results to samples from human lungs. Did any of your findings surprise you?
Shravani Pasupneti: Yeah, there were a few really interesting things, actually. The first time I saw some of the fusion results, I was actually really amazed. I expected that the history knockouts explosive fusion would have emphysema, but I wasn't expecting it to be so much more profound in what we saw the fusion animals load.
But even more interesting was what we saw in the setting of HIF-2 overexpression, so I didn't expect that HIF-2 overexpression would prevent disease in the fusion model. And this is really exciting because it could have real implications for patient care.
The [indecipherable 3:11] inhibitors, which results in HIF-1 and HIF-2 expression, consecutively already exist and are in the market and being studied as treatment options for management of CKD-related anemia. And so given that these drugs already exist and what we found, it shows that there might be clear therapeutic potential for some of the things that we're seeing.
The other thing that was really surprising to me was in our human studies or in the human samples. And what we saw was that not only were there fewer endothelial cells in the COPD sample but also the endothelial cells that remained.
Specifically, in the patients with advanced COPD, those cells had even lost HIF-2, suggesting that HIF-2 is actually one of the key drivers responsible for the pathology and not just the reduction of endothelial cell number.
Amanda Balbi: How do these findings add to the existing body of literature?
Shravani Pasupneti: I think there's a few key points to take away from our work. The first is really that HIF-2 is essential, I think, for the pathogenesis for emphysema. Previous studies have shown that tobacco smoke leads to a reduction in HIF-2, and it's well-accepted that tobacco is one of the most important risk factors for emphysema.
Our genetic model shows that this induced loss of endothelial HIF-2α, as you can get from tobacco smoke exposure, results in emphysema. And so, our genetic model is very clearly clinically relevant.
Another interesting thing we found was about HIF-2 deletion results in a reduction of endothelial cells and pericytes. The pericytes I think are really interesting, because we know that pericytes are important in maintaining albulor health. And so, this just helps us think about one of the mechanisms that might be necessary or that might be responsible for the observed phenotype.
The last thing we showed was that HIF-2 overexpression is able to overcome the [indecipherable 4:52] antagonism that you see from that you see from [indecipherable 4:54], suggesting that modulating HIF-2 can prevent disease. These fusion HIF-2 things are actually especially interesting because there's a lot of interest in fusion and HIF-2, especially in the world of pulmonary hypertension.
So we know that [indecipherable 5:08] in combination with chronic hypoxia results in pulmonary hypertension. There's a fair amount of evidence that suggests that decreased HIF-2 is protective in hypoxia-induced PH, and as a result of that, there's actually medications that are being studied to decrease HIF and possibly use the therapies for PH.
Given our findings, I think it suggests that any therapies that we use to inhibit HIF should be really carefully studied to monitor for any obstructive lung disease as what we saw in our study.
Amanda Balbi: How might these findings help improve care for patients with emphysema or are at high risk for emphysema?
Shravani Pasupneti: We know that endothelial HIF-2 is an endogenous factor that prevents the development of emphysema. Our findings are also supported by the fact that our model resulted as an epidemic phenotype that’s similar to aging-associated COPD, where the phenotype is predominantly in the alveoli region, rather than bronchial inflammation.
And since we know that tobacco smoke also results in damage to endothelial cells and reduction in HIF-2, it strongly supports the idea that HIF-2 could be a key potential target for interventions to protect at risk patients.
Amanda Balbi: In your opinion, how do you hope your findings will impact the future of patient care?
Shravani Pasupneti: I think our findings are actually really exciting, and the reason I feel that is that we've shown really for the first time that modulating the expression of one gene—HIF-2—can prevent emphysema.
Our results are especially clinically applicable given not tobacco smoke is one of the most significant risk factors for the development of emphysema, and we know tobacco smoke exposure results in decreased pulmonary HIF-2.
Given the shortage of curative options for people with COPD. I'm really hopeful that our study will help lead to more definitive therapies for patients who are suffering from this chronic condition and don't really have other options for treatment.
Amanda Balbi: Great, thank you again for speaking with me today and answering all my questions.
Shravani Pasupneti: Of course, thank you so much for this opportunity. It's great to share and looking forward to working on this further.