According to the World Health Organization (WHO) pulmonary diseases are the fourth cause of death worldwide.
Third cause of death in the USA, Europe and Japan.
Chronic Obstructive Pulmonary Disease (COPD)
COPD is characterized by remolding of the lung architecture that typically results in airspace enlargement (emphysema).
Currently there are very limited treatment options for COPD, with the only viable option being lung transplantation.
Thus, our lab aims to identify the mechanisms that lead to the remodeling of the lungs in COPD in order to develop new therapies to interrupt the progression of disease and reduce mortality.
Idiopathic Pulmonary Fibrosis (IPF)
IPF is a lethal lung disease of
unknown etiology defined by chronic, progressive and irreversible interstitial fibrosis (scarring).
This scarring process slowly obliterates the alveoli of the lung, preventing patients to obtain oxygen from the air they breathe.
IPF has a high mortality rate of up to 80% underscoring the need to develop novel therapies to treat this fatal disease.
Our lab focuses in understanding new molecular pathways that are important in the development of pulmonary fibrosis.
Pulmonary Hypertension (PH)
PH is a common complication of chronic lung diseases including IPF or COPD.
PH can also be associated with cardiovascular conditions such as left-heart disease or appear completely own its own.
In all of these cases the diagnosis of PH is strongly associated with increased mortality and there are limited treatment options.
The mission of our lab is to understand the mechanisms that lead to the development of PH in order to discover new treatments
What are the mechanisms that lead to chronic lung disease?
Our research efforts focus on three main topics:
1. Understanding how changes in the lung extracellular matrix (ECM) lead to vascular remodeling in PH associated with IPF
The presence of PH in patients with IPF is the single most significant predictor of mortality, yet there are no cures at present that effectively prevent or treat PH in patients with IPF. In this project we have identified increased levels of hyaluronan, a component of the lung ECM, in the lung of patients with a diagnosis of PH associated with IPF. We next demonstrate that the increase in hyaluronan is mediated by an elevation in hyaluronan synthase 2 (HAS2), an enzyme that makes hyaluronan. Finally we demonstrate that treatment with 4 methyl-umbelliferone (4MU), a drug that inhibits HAS2, is able to reduce levels of hyaluronan and treats PH associated with lung fibrosis. We are currently examining the mechanisms that lead to HAS2 increases in patients with IPF and examining how selective deletion of HAS2 from smooth muscle cells contributes to the development of PH.
2. Evaluating how changes in mRNA 3’UTR length participates in the development of COPD.
In collaboration with leaders in RNA-biology and with Dr. Leng Han, an expert in bio-informatics at UTHealth, we have identified changes in the 3’UTR length of mRNAs in patients with COPD. These mRNAs encode many proteins associated with the development of disease. In addition, we show that a protein known as cleavage factor 25 (CFIm25) regulates the length of the 3’UTRs and that depletion of this protein results in global shortening of mRNAs. This protein was also found to be depleted in patients with COPD. Our research efforts are aimed at elucidating how 3’UTR shortening contributes to the development of COPD, using tissue samples from the UTHealth Pulmonary Center of Excellence bio-bank and sophisticated experimental models of disease. In addition to this, our data also shows reduced levels of CFIm25 in remodeled vessels in PH occurring on its own (Group I) or associated with chronic lung diseases (Group III). Little is known of the role of CFIm25 in lung diseases.
3. Determining how differential loss of bone-morphogenetic-protein-receptor 2 (BMPR2) in cells of the lung lead to disease progression in IPF.
Mutations in bone-morphogenetic-protein-receptor 2 (BMPR2) resulting in the loss of function of this receptor have been strongly linked with the development of pulmonary arterial hypertension. Yet, whether loss of function of this protein participates in the development of other lung diseases is not fully understood. Research from our lab shows that BMPR2 levels are depleted in patients with IPF and in experimental models of lung fibrosis. Our research shows that maintaining the expression of BMPR2 protects against the development of lung fibrosis. We are currently investigating how depletion and cell-specific loss-of-function of BMPR2 contributes to the pathogenesis of disease.
Our most recent and selected publications are highlighted here
Switching-Off Adora2b in Vascular Smooth Muscle Cells Halts the Development of Pulmonary Hypertension
Vascular ADORA2B expression modulates PH
Using mice lacking ADORA2B in smooth muscle cells, we demonstrate that this receptor is necessary for the development of PH induced by bleomycin or by hypoxia-sugen. The novel mechanism involves Adora2b-mediated increased expression of tissue trans glutaminase (TGM2) and hyaluronan synthase 2 (HAS2).
Inhibition of Hyaluronan Synthesis Attenuates Pulmonary Hypertension Associated with Lung Fibrosis
Elevated vascular hyaluronan leads to pulmonary hypertension in the context of lung fibrosis
Here we identify a unique mechanism leading to pulmonary hypertension in the context of lung fibrosis that is mediated by elevated vascular hyaluronan. Here we also show how the hyaluronan synthesis inhibitor, 4MU, prevents the development of pulmonary hypertension.
Pulmonary Hypertension Associated with Idiopathic Pulmonary Fibrosis: Current and Future Perspectives
Here we review the current understanding of the mechanisms known to lead to Group III pulmonary hypertension
In this review we have chosen to focus on the current understating of PH in IPF, we will revisit the main mediators that have been shown to play a role in the development of the disease. We will also discuss the experimental models available to study PH associated with lung fibrosis and address the role of the right ventricle in IPF.
Macrophage bone morphogenetic protein receptor 2 depletion in idiopathic pulmonary fibrosis and Group III pulmonary hypertension
This is one of the first papers to identify depletion of BMPR2 in IPF
Here we demonstrate that BMPR2 is depleted in IPF and in experimental lung fibrosis. We also demonstrate that IL-6 signalling leads to a cascade of micro-RNAs (miRs) that target the BMPR2 mRNA for degradation.
Altered Hypoxic-Adenosine Axis and Metabolism in Group III Pulmonary Hypertension.
Elevations in succinate activate the hypoxic-adenosine axis
Here we show that alterations in metabolism in patients with IPF and PH lead to heightened stabilization of hypoxia-inducible factor 1 (HIF-1A). HIF-1A then drives the expression of CD73 resulting in augmented adenosine production and signaling through the adenosine A2B receptor (ADORA2B), modulating disease progression.
Deletion of ADORA2B from myeloid cells dampens lung fibrosis and pulmonary hypertension
ADORA2B in macrophages modulates both fibrosis and PH
In this article we demonstrate that genetic deletion ADORA2B from macrophages leads to lessening of fibrotic deposition and reduced right ventricle systolic pressures (RVSP), a readout of pulmonary hypertension in mice. We also show that depletion of macrophage ADORA2B expression leads to a reduction in alternatively activated macrophages.
Adenosine A2B receptor and hyaluronan modulate pulmonary hypertension associated with chronic obstructive pulmonary disease.
ADORA2B regulates vascular hyaluronan production
Here we demonstrate that patients with COPD and PH have elevated hyaluronan levels. This is also replicated in an experimental model of chronic lung injury and PH using the adenosine deaminase deficient (Ada-/-) mice. We show using in vivo and in vitro assays that blockade of ADORA2B signaling results reduced hyaluronan and expression of hyaluronan synthases (HAS).
The A2B adenosine receptor modulates pulmonary hypertension associated with interstitial lung disease
Pharmacological or genetic abrogation of ADORA2B inhibits PH
Using an ADORA2B antagonist or a global ADORA2B knock-out mice, we demonstrate that supressing ADORA2B signalling diminished experimental lung fibrosis and PH.
Get to know us!
Harry Karmouty-Quintana, PhD
Harry received his undergraduate degree in Pharmacology
from King’s College London (UK) in 2003. In 2006, he received his PhD in
Pharmacology and Biophysics from King’s College London (UK) where he pioneered the use of Magnetic Resonance Imaging (MRI) as a tool to non-invasively image experimental lung disease. His PhD was a joint venture between King’s College London and Novartis Pharmaceuticals, located in Basel, Switzerland. From 2006-2010 he was a Postdoctoral Fellow at McGill University where he was funded by the Fonds de la Recherche en Santé du Québec (FRSQ). He then joined UTHealth in 2010 as Postdoctoral Fellow where he was funded by the American Heart Association (AHA). He was promoted as a Research Track Assistant Professor in 2012 and in 2015 he became a Tenure-Track Assistant Professor at UTHealth. Originally from Barcelona, he may be hard to find if FC Barcelona is playing a Tournament Final!
Weizhen Bi, MD
Senior Research Associate
Weizhen is originally from Liaoning Province in China. She joined the Karmouty Lab in September 2017. Weizhen completed her MSc and MD at China Medical School in ShenYang. She joined The McGovern Medical School at UTHealth as a postdoctoral fellow in 1993 and has since gained extensive expertise in tumor cell biology, vascular development and atherosclerosis. Since 2001, she worked in Dr. Joseph Alcorn's lab at UTHealth where she gained experience in lung cell biology and the role of surfactants in lung immunology. On her free time Weizhen enjoys spending time with her family and preparing traditional Chinese dishes.
Scott D Collum
Scott is from Huckaybay, TX where he graduated first in his class from Huckaybay ISD and where he learned to raise farm animals. He then moved to college station where he graduated summa cum laude with a B.S. in Biochemistry from Texas A&M University. He then moved Houston to pursue his PhD at UTHealth in RNA biology and pulmonary diseases. Scott is an avid runner and completed his first marathon in December 2016. If you are looking for the best donuts in town, he is the person to ask!
Tinne C Mertens, PhD
After she finished her Master degree in biomedical sciences at Hasselt University in Belgium, Tinne moved to Amsterdam in the Netherlands and started her PhD training at the Leiden University Medical Center. During her Master and PhD training, she worked extensively with in vitro air-liquid interface airway epithelial cell cultures of both animal and human origin. Next, she moved to Houston and joined the lab in June 2016 where she had the opportunity to work with in vitro cultures of human transplant and explant tissues in addition to translational experimental models of chronic lung disease. Combining in vitro cultures and in vivo models allows her to investigate of role specific cell types in the development of chronic lung disease and identify possible therapeutic targets, something I am very passionate about.
Tinne loves traveling and learning new things about countries, their cultures and the people. She enjoys indoors rock climbing together with her husband and friends.
Cory is from Little Elm, TX. He completed his BSc in Biochemistry from the University of Houston. He then joined the MD/PhD program at the MDAnderson / UTHealth Graduate School of Biomedical Sciences, he joined the Karmouty Lab in September 2017 where his project aimed to identify developmental re-programming in chronic lung disease. Cory enjoys cooking and is a BBQ connoisseur.
Summer Research Program Student - 2016 and 2018
Ankit is a pre-medical student at the University of Texas at Austin from Dallas. He describes himself as a history buff with a knack for science. In the future, he aims to pursue a MD degree to understand diagnoses and help improve upon them through science.
Lab Outing to Top Golf
Tamara Darwiche, Melissa Chavez Lauren Headley and Adriana Hernandez (1st row on the left) have since left the lab but remain active in science careers. Not pictured Amara DiFrancesco is now a veterinary student at Cornell University
Recent accomplishments from the Lab
Tinne's 1st first-author original contribution from the Karmouty Lab!
Background: Pulmonary hypertension (PH) is a devastating and progressive disease characterized by excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and remodeling of the lung vasculature. Adenosine signaling through the ADORA2B receptor has previously been implicated in disease progression and tissue remodeling in chronic lung disease. In experimental models of PH associated with chronic lung injury, pharmacological or genetic inhibition of ADORA2B improved markers of chronic lung injury and hallmarks of PH. However, the contribution of ADORA2B expression in the PASMC was not fully evaluated.
Hypothesis: We hypothesized that adenosine signaling through the ADORA2B receptor in PASMC mediates the development of PH.
Methods: PASMCs from controls and patients with idiopathic pulmonary arterial hypertension (iPAH) were characterized for expression levels of all adenosine receptors. Next, we evaluated the development of PH in ADORA2Bf/f-Transgelin (Tagln)cre mice. These mice or adequate controls were exposed to a combination of SUGEN (SU5416, 20mg/kg/b.w. IP) and hypoxia (10% O2) for 28 days (HX-SU) or to chronic low doses of bleomycin (BLM, 0.035U/ kg/b.w. IP). Cardiovascular readouts including right ventricle systolic pressures (RVSPs), Fulton indices and vascular remodeling were determined. Using PASMCs we identified ADORA2B-dependent mediators involved in vascular remodeling. These mediators: IL-6, hyaluronan synthase 2 (HAS2) and tissue transglutaminase (Tgm2) were determined by RT-PCR and validated in our HX-SU and BLM models.
Results: Increased levels of ADORA2B were observed in PASMC from iPAH patients. ADORA2Bf/f-Taglncre mice were protected from the development of PH following HX-SU or BLM exposure. In the BLM model of PH, ADORA2Bf/f- Taglncre mice were not protected from the development of fibrosis. Increased expression of IL-6, HAS2 and Tgm2 was observed in PASMC in an ADORA2B-dependent manner. These mediators were also reduced in ADORA2Bf/f- Taglncre mice exposed to HX-SU or BLM.
Conclusions: Our studies revealed ADORA2B-dependent increased levels of IL-6, hyaluronan and Tgm2 in PASMC, consistent with reduced levels in ADORA2Bf/f- Taglncre mice exposed to HX-SU or BLM. Taken together, our data indicates that ADORA2B on PASMC mediates the development of PH through the induction of IL-6, hyaluronan and Tgm2. These studies point at ADORA2B as a therapeutic target to treat PH.
Scott's 1st first-author original contribution
Group III Pulmonary hypertension (PH) is a highly lethal and widespread lung disorder that is a common complication in idiopathic pulmonary fibrosis (IPF) where it is considered to be the single most significant predictor of mortality. While increased levels of hyaluronan have been observed in IPF patients, hyaluronan-mediated vascular remodelling and the hyaluronan-mediated mechanisms promoting PH associated with IPF are not fully understood.EXPERIMENTAL APPROACH:
Explanted lung tissue from patients with IPF with and without a diagnosis of PH was used to identify increased levels of hyaluronan. In addition, an experimental model of lung fibrosis and PH was used to test the capacity of 4-methylumbeliferone (4MU), a hyaluronan synthase inhibitor to attenuate PH. Human pulmonary artery smooth muscle cells (PASMC) were used to identify the hyaluronan-specific mechanisms that lead to the development of PH associated with lung fibrosis.KEY RESULTS:
In patients with IPF and PH, increased levels of hyaluronan and expression of hyaluronan synthase genes are present. Interestingly, we also report increased levels of hyaluronidases in patients with IPF and IPF with PH. Remarkably, our data also show that 4MU is able to inhibit PH in our model either prophylactically or therapeutically, without affecting fibrosis. Studies to determine the hyaluronan-specific mechanisms revealed that hyaluronan fragments result in increased PASMC stiffness and proliferation but reduced cell motility in a RhoA dependent manner.CONCLUSIONS AND IMPLICATIONS:
Taken together, our results show evidence of a unique mechanism contributing to PH in the context of lung fibrosis.
New R01 Funding!
3’UTR shortening in Pulmonary Vascular Disease
8 percentile score on first submission!
Pulmonary hypertension is a disorder of the pulmonary vasculature defined by increased mean pulmonary arterial pressure (mPAP) leading to right-sided heart failure and ultimately death with 3 to 5 years of diagnosis; it can appear on its own or in association with chronic lung diseases. This proposal examines the mechanisms by which a process known as Alternative Polyadenylation leads to 3’UTR shortening contributing to vascular remodeling in PH. Knowledge obtained from these studies could lead to novel therapeutic options for patients suffering from pulmonary hypertension.
At the forefront of Pulmonary Disease Research through access to highly valuable patient material and solid collaborations with physician scientists.
Memorial Hermann and Houston Methodist Research Institute
We collaborate closely with physician scientists at Memorial Hermann Hospital and Houston Methodist Hospital systems, making advances in translational research. Through these collaborations, Dr. Karmouty Quintana directs the UTHealth Pulmonary Center of Excellence lung tissue biobank. This Biobank is one of the largest in the country and it houses lungs from patients with COPD, IPF, Pulmonary Hypertension in addition to other lung diseases.
Local and International Network of Collaborators
We collaborate with many basic-science laboratories locally and internationally to advance our understanding of how lung diseases develop with the hope of developing new treatments for disease. Current collaborations include the use of nanoparticles for gene-therapy for lung injury, microbiome research in patients with chronic lung injury and applying bio-informatics for lung research.
Current and Past Funding
1R01 HL138510-01 (PI: Karmouty-Quintana)
3’UTR shortening in Pulmonary Vascular Disease
The goal of this project is to examine the effects of alternative polyadenylation in the development of pulmonary hypertension.
Biomedical Research Grant
RG-414673 (PI: Karmouty-Quintana)
Alternative Polyadenylation in the pathogenesis of COPD
The goal of this project is to examine the contribution of alternative polyadenylation in the pathogenesis of COPD
Call for Grants Notification in IPF
G-45857 (PI: Karmouty-Quintana)
BMPR2 in Acute and Chronic Lung Injury.
The goal of this project is to examine the contribution of bone morphogenic protein receptor 2 (BMPR2) in acute and chronic lung injury
UTHealth Pulmonary Center of Excellence
Discovery Award (PI: Karmouty-Quintana)
CfIm25 links alternative polyadenylation with pulmonary hypertension and right ventricle hypertrophy
The goal of this project is to understand the contribution of CFIM25 and its role in alternative polyadenylation in the pathogenesis of pulmonary hypertension
Scientist Development Grant
14SDG18550039 (PI: Karmouty-Quintana)
The role of hyaluronan in pulmonary hypertension secondary to lung fibrosis
This project focuses on understanding the contribution of hyaluronan in the development of pulmonary hypertension secondary to chronic lung diseases.
Entelligence MD Actelion Award
The role of hyaluronan in pulmonary hypertension associated with idiopathic pulmonary fibrosis (IPF)
The project focused on understanding the contribution of hyaluronan in the development of pulmonary hypertension secondary to chronic lung diseases.