Dr. Harry Karmouty-Quintana is a PI in the Department of Biochemistry and Molecular Biology at the University of Texas Health Science Center of Houston. The Karmouty lab studies the mechanisms behind vascular remodeling and fibrosis as well as pulmonary hypertension associated with chronic lung diseases. Specifically, the lab is interested in how adenosine, hyaluronan and a novel developmental gene called Six1 contribute to these pathologies. His lab is at the forefront of preclinical chronic lung disease research and we were able to sit down with him to learn more about his work and get his thoughts on the current state and future of preclincial pulmonary fibrosis research!
I started the pulmonary field because my degree included a year in industry, and I happened to do it at Novartis in the lab of Drs. John Fozard and Lazzaro Mazzoni that was focused on Airway Hyperresponsiveness – so that was my first interaction with the Pulmonary Field and I have not left it since. We were doing lung function in those days. I stayed in the pulmonary field because there aren’t many therapies for lung diseases in general, and very limited treatments available for CLDs. So there seemed to be a need here, and I was interested in the science. At this time I was very impressed with the role of adenosine, so this is how I originally got into adenosine research. It was one of the few molecules that you could really tell if a mouse was asthmatic lets say, because you would have a strong bronchorestrictive response to adenosine in lung function that was not present in naïve mice.
There is a lot of interest right now in single cell sequencing and in that area one of the hottest parts is the role of progenitor cells and how they may contribute to the development of disease by either promoting disease or by not being enough of those cells available to repair the lung.
This is an interesting question, because I mostly do pre-clinical research, so real-world implications are a little bit far off on the horizon. We are now working with some targets that we hope will one day reach patients. We are really targeting pathways that are involved in promoting remodeling. One of the most real-word interactions of my research is that we collect a lot of lung explants from IPF or CLD patients that have had a lung transplant. It is very fascinating to get access to these end-stage lung diseased lungs, and you can really see the extensive amount of remodeling that happens. It is a real eye-opener to see what kinds of challenges that can happen in a pre-clinical area that we need to overcome to try and bring some reconstructive lung therapy in these patients.
I have been a SCIREQ user since my post-doc at McGill University in Dr. James Martin’s lab where my research focused in understanding how sphingolipids contributed to chronic asthma.
We like the intraperitoneal model of bleomycin-induced lung fibrosis because the injury that appears in mice is more of a subpleural origin – starts in the subpleural area and moves in. This is more reminiscent of how patients with IPF present; with subpleural fibrosis that moves into the main airways. In the Intratracheal (IT) method, you find a fibrosis that is more peribroncheal, which is different than the classic clinical presentation of IPF. But it is bleomycin – so the field has a love/hate relationship with this model!
There are other models out there that we are trying to get into, which I think are a lot more clinically relevant. There are two mouse models that replicate some of the common genetic deficits that people develop in IPF. For instance, surfactant protein C mutations, where these mice develop spontaneous lung fibrosis. There is also a TRF mouse which lack a shelterin component for telomerase, so these mice also develop spontaneously lung fibrosis. So I think these two models are very clinically relevant but the drawback is that it can take up to 9 months to present with fibrosis. There are not too many publications out there with these two models at the moment – which is interesting – because they are not easy to access and they are hard to develop.
The flexiVent has been really great for us because our IP model takes about 4 weeks to develop, and we have been able to show early changes in some of the lung function parameters at very early time points. In my lab’s 2018 publication, we show that functional changes such as overall resistance, compliance, elastance and pressure volume loops show impairment following day 7 of IP bleomycin. This functional data was paired with histological gene expression and fibrotic deposition changes in this group as well at day 7. This reinforces that pre-clinical lung function can be a robust and physiologically relevant tool to identify early critical windows for therapeutic intervention. This makes it much more sensitive than invasive techniques like histology which are normally done, or pro-fibrotic mediators by qPCR in isolated lungs. So the flexiVent has been really useful for us so then we can try and target therapy a little bit earlier.
Also we have the new Forced Expired Volume (FEV) extension, which is great because now we can have FEVx and Forced Vital Capacity (FVC) measurements which are really clinically translatable. Sometimes with the pre-clinical lung function parameters, when you explain these parameters to clinicians, they are a bit confused because these are not parameters that they are super accustomed to hear about. But having FEV and FVC, it is much better to grasp the clinical relevance of these studies and it makes it much more translatable overall.
Right now we are in this exciting area of trying to understand the pathology of Covid-19. What’s fascinating with this virus is that it is able to cause a lot of rapid progression of disease. Some of the reports I have been reading is that some of the patients that recover from Acute Respiratory Distress Syndrome (ARDS) they develop lung fibrosis very fast. Typically, people that survive ARDS, they may over a period of several years develop fibrosis. But in these Covid patients, these seems much more rapidly induced, which is due to a lot of the pathways that are upregulated. So they present with severe hypoxemia, also a lot of thrombotic processes, and I think these two together may promote a much more enhanced fibrotic condition. That’s one of the things that I thin would be very interesting to understand the pathophysiology of this virus leads to this pretty devastating lung conditions.
I review a few grants fibrosis field. There are a few papers (referenced below) by the Red Journal that is a very good guide for pre-clinical research in lung fibrosis. This paper explains the advantages of the different models, and incorporate things like should you look at gender differences and at what stage you should look at different factors in your drug discovery or mechanistic platform. So starting out with these reviews for the best practices and guides are probably the best approach.
Jenkins, R.G., et al. (2017). An Official American Thoracic Society Workshop Report: Use of Animal Models for the Preclinical Assessment of Potential Therapies for Pulmonary Fibrosis. Am J Respir Cell Mol Biol. 56(5): 667–679.
Thank you Dr. Karmouty-Quintana for taking the time to do this interview! If you would like to learn more about the Karmouty Lab and their research, check out the lab website here!
Rao, W., Karmouty-Quintana et al. (2020). Regenerative Metaplastic Clones in COPD Lung Drive Inflammation and Fibrosis. Cell, In Press, doi.org/10.1016/j.cell.2020.03.047
Wang, W., Wilson, C., Collum, S., Bi, W., Ko, J., Rajagiopal, K., Karmouty-Quintana, H. (2020). Beta Adrenoceptor Ligands for the Treatment of Group 3 Pulmonary Hypertension and Cor Pulmonale: A Novel Therapeutic Target? The Journal of Heart and Lung Transplantation, 39(4): 169
Weng T, Karmouty-Quintana Crystal Deposits in Macrophages and Distal Lung Remodeling: A Tale of Aging in SFTPC-Deficient Mice. Am J Respir Cell Mol Biol. 2020 Apr;62(4):405-406. doi: 10.1165/rcmb.2020-0018ED. No abstract available.
Collum, S.D., Molina, J.G., Hanmandlu, A., Bi, W., Pedroza, M., Mertens, T.C.J., Wareing, N., Wei, W., Wilson, C., Sun, W., Rajadas, J., Bollyky, P.L., Philip, K.M., Ren, D., Thandavarayan, R.A., Bruckner, B.A., Xia, Y., Blackburn, M.R, Karmouty-Quintana H. (2019). Adenosine and hyaluronan promote lung fibrosis and pulmonary hypertension in combined pulmonary fibrosis and emphysema. Dis Model Mech. 12(5). pii: dmm038711. doi: 10.1242/dmm.038711.
Rajagopal, K., Byrant, A.J., Sandeep, S., Wareing, N., Zhou, Y., Pandit, L.M., Karmouty-Quintana H. (2020). Idiopathic pulmonary fibrosis and pulmonary hypertension: Heracles meets the Hydra. BPJ, https://doi.org/10.1111/bph.15036
Weng, T., Karmouty-Quintana H. et al. (2019). Cleavage factor 25 deregulation contributes to pulmonary fibrosis through alternative polyadenylation. JCI, doi 10.1172/JCI122106
Headley, L., Karmouty-Quintana H. et al. (2018). Low‐dose administration of bleomycin leads to early alterations in lung mechanics. Experimental Physiology, https://doi.org/10.1113/EP087322