Dr. Ambalavanan is a board-certified physician-scientist in Pediatrics and Neonatal-Perinatal medicine. He currently serves as Professor and Director of the Translational Research in Normal and Disordered Development (TReNDD) Program and the Division of Neonatal Research at the University of Alabama at Birmingham. On this segment of Meet The Experts, we speak with Dr. Ambalavanan about what drives his research forward.
I started off doing a residency in Pediatrics and then I realized I wanted to do Neonatology. It’s a very “high risk – high reward” kind of a part of Pediatrics. It’s a lot of dealing with critical care in Pediatrics and that’s more like my personality. I want to do things quickly, have results fast and you’re able to do such things in PICU, NICU and basically the critical care aspects of Pediatrics.
In neonatology you are taking care of multiple organ systems. It’s not just like you’re taking care of the heart like a cardiologist, blood counts like a hematologist or seizures like a neurologist. In this field, you are taking care of multiple organ systems and you’re taking care of a critically ill patient. Babies, fortunately, are quite resilient and often do get better. So, it’s a very rewarding profession too.
Most of my research is focused on lung development and lung injury, and one of the problems we face commonly in the neonatal ICU is chronic lung disease in preterm babies. We call that bronchopulmonary dysplasia. These are lung development issues because the lungs are exposed to too much oxygen, too much mechanical ventilation, and it’s also contributed to by infections, inappropriate nutrition and so forth. So that’s something we in neonatology have been trying to investigate for many decades, and we have found that it’s primarily an inhibition of lung development, but also some amount of fibrosis and inflammation.
Devices like the flexiVent are key because we want to quantify the magnitude of inhibition and lung development, both in terms of lung mechanics and histology.
I think we are trying to first identify the mechanisms by which the normal lung develops and how this mechanism is disrupted during abnormal lung development. We test multiple agents that that modulate signaling pathways. So, we have looked at different pathways such as TGF beta, endothelin pathway, various microRNAs, etc.
The goal is to improve lung development when the lung has been exposed to various injuries, which is sometimes difficult to do in humans. It is not like you can study most agents as investigational drugs in newborn babies without first testing them in older kids or having a good safety track record. So, most of our research is actually in animal models, but then eventually we hope to move some of them to the clinic.
We have been flexiVent users since 2007-2008. The flexiVent is a very good tool for looking at lung mechanics in small animal models. It’s quite a reproducible measurement, because you do not need many subjects to get tight, quality data such as resistance and compliance.
Some of the parameters like, say the tissue G&H and all those, they can vary a bit, but I think the compliance and resistance overall really don’t change very much and it’s really useful because you can see the effects of even small changes between groups. For instance, if you expose mice to hyperoxia or to other inflammation, you can see the effects on the lung mechanics quite quickly. The differences are quite substantial, it’s more like a 30 or 40% a difference rather than 10%.
The flexiVent has helped to confirm what we already know in terms of BPD and neonatal chronic lung disease, such as inhibition of lung development and decreased compliance after exposure to high oxygen. The lungs become stiffer and increase in both central and distal airway resistance. This is consistent with what we know in preterm babies.
Additionally, we have done some studies with retinoids such as vitamin A and we have shown even in humans that vitamin A is able to reduce BPD and retinoids in mouse models also improve lung mechanics.
I think the first thing is that they need to realize that’s a lot we don’t know. There are a lot of concepts which are extrapolated from what we know in adults or older children, which may not be correct in neonates. So, there’s a lot of checking of assumptions that need to be made before we actually start a research project, because you don’t want to go halfway down the project before you realize some of the underlying assumptions are not accurate. You need to check all the underlying assumptions.
Secondly, I think important to go where the data are taking us, meaning that we don’t want to do studies just to confirm our own bias. We actually want to look at the data and try to reproduce what we do find. The goal is to identify a mechanism rather than trying to confirm your hypothesis that may be incorrect. You want to be data driven, rather than just testing a hypothesis.
I do a lot of different types of research, and it’s not just focused on the lung. We do work related to the kidney, to neurodevelopment, we are doing work on the microbiome and we are also trying to actually develop an integrated model where we bring together data from transcriptomics, proteomics, histology and lung mechanics.
We’re trying to bring it all together into an integrated model because looking at pediatric diseases or disorders through just one perspective, you kind of tend to not see the whole disease in a holistic model. You want to look at everything together; functional, pathophysiological, and histological. I think we are trying to do that currently and hopefully we’ll do more of that in the future, have a more integrated model.
Vamesu, Bianca M., et al. “Thyroid hormone modulates hyperoxic neonatal lung injury and mitochondrial function.” JCI insight 8.8 (2023).
Kandasamy, Jegen, et al. “Mitochondrial DNA variation modulates alveolar development in newborn mice exposed to hyperoxia.” American Journal of Physiology-Lung Cellular and Molecular Physiology 317.6 (2019): L740-L747.
Abdelgawad, Ahmed, et al. “Antimicrobial peptides modulate lung injury by altering the intestinal microbiota.” Microbiome 11.1 (2023): 226.
