The Division of Pediatric Pulmonology directs investigator-initiated basic and clinical research programs related to asthma, cystic fibrosis and bronchopulmonary dysplasia. Faculty research is funded by the National Institutes of Health and Cystic Fibrosis Foundation. Areas of study include:
Asthma
- Viral-induced exacerbations of asthma and other chronic airways diseases
- Contribution of early-life respiratory viral infections in the development of asthma
- Matricellular proteins in the pathogenesis of asthma and bronchopulmonary dysplasia
- Interactive effects of diesel exhaust and respiratory viral infection on asthmatic children
- Promoting activity among children with asthma in Detroit
Cystic Fibrosis
- Role of viral and bacterial co-infection in the pathogenesis of cystic fibrosis lung disease
- Influence of the airway microbiome on nontuberculous mycobacterial infection in cystic fibrosis
- Interventions to improve adherence in children with cystic fibrosis
- Studies to improve the cystic fibrosis newborn screening parental notification process
Bronchopulmonary dysplasia
- Matricellular proteins in the pathogenesis of asthma and bronchopulmonary dysplasia
- Damage-associated molecular patterns and priming of the immune system in bronchopulmonary dysplasia
- Role of adipose-tissue macrophages in the pathogenesis of obesity-associated diseases such as metabolic syndrome and diabetes
Faculty Research Interests
Carey N. Lumeng, M.D., Ph.D.
Obesity threatens the health of children and adults in the U.S. due its strong association with diseases such as metabolic syndrome and Type 2 diabetes. My laboratory studies the origins of adipose tissue inflammation with obesity. My current research projects include:
Regulation of adipose tissue inflammation by antigen presenting cells
Recently, studies have demonstrated that T cells partner with adipose tissue macrophages (Figure) to cause inflammation in obese adipose tissue. We are trying to identify the types of cell-cell communications that regulate inflammation in adipose tissue can identify novel points for intervention to uncouple obesity from its negative effects on health.
Inflammation in adipose tissue and health in obesity
In collaboration with Dr. Robert O’Rourke MD we are interested in the role adipose tissue macrophages play in metabolic regulation in obese humans and how adipose tissue inflammation differs from individuals with healthy and unhealthy obesity.
Identification of the types of cell-cell communications that regulate inflammation in adipose tissue can identify novel points for intervention to uncouple obesity from its negative effects on health.
Extracellular matrix and adipocyte biology
This project is interested in understanding the links between the extracellular matrix and metabolic control in obese humans.
J. Kelley Bentley, Ph.D.
The focus of my research is the immunology and pathophysiology of respiratory viral infections and their contribution to the exacerbation of airways disease. My work uses cell culture and mouse models of asthma in collaboration with Dr. Marc Hershenson. We are currently studying rhinovirus, enterovirus D68, and human coronavirus NL63, a relative of SARS-CoV2.
We recently discovered that Toll-like receptor 2 (TLR2) is required for rhinovirus--A1B infections in cellular and in vivo mouse systems, and that viral protein 4 (VP4) is the likely ligand (see Figure). Future studies will examine whether TLR2 is a common co-receptor for different enteroviruses, including the new rhinovirus species RV-C.
Funding: R56 AI150660 and R01 AI134369
Lindsay J. Caverly, M.D.
The focus of my research is the airway microbiome in people with cystic fibrosis, particulary
those with non-tuberculous mycobacterial (NTM) infection. The prevalence of NTM infection (including Mycobacterium abscessus and Mycobacterium avium complex) is increasing in people with cystic fibrosis.
NTM is a particularly challenging infection, as it can lead to significant lung function decline. In addition, treatment may have significant side effects (primarily ototoxicity), and may not be completely effective. My goal is to identify infectious and inflammatory changes in cystic fibrosis airways that are predictive of NTM infection and disease course. My research is funded by the Cystic Fibrosis Foundation (Harry Shwachman and Clinical Research Awards, and Clinical Research Scholars Program (CRSP) and the NIH (K23 award).
Marc B. Hershenson, M.D.
The focus of my research is chronic airways disease in children, including asthma, cystic fibrosis and bronchopulmonary dysplasia. Specific research projects include:
Viral-induced asthma exacerbations
My laboratory developed the first mouse model of rhinovirus-induced asthma exacerbations.
Using this model, we found for the first time that rhinovirus interacts with not only airway epithelial cells but also non-resident airway macrophages, perhaps explaining the brisk inflammatory response to viral infection in asthmatics compared to normal subjects. We have also found interactions between rhinovirus and macrophages in human airways. We are currently studying a new rhinovirus species that causes more severe asthma attacks called rhinovirus C (Figure).
Early-life viral infections in the development of asthma
Early-life wheezing-associated respiratory viral infections have been recognized to be a harbinger of asthma in young children. However, it is unclear whether viral infections, in combination with other factors, actually contribute to asthma development, or whether viral infection simply unmasks asthma that was already present. To study this, my laboratory developed the first immature mouse model of rhinovirus infection.
We found that early-life infection of immature mice with rhinovirus causes a long-lasting
asthma phenotype consisting of mucous metaplasia and airways hyperresponsiveness which is dependent on IL-13, IL-25 and type 2 innate lymphoid cells (Figure).
Interestingly, the pro-asthmatic effect of virus is limited to mice that are less than 8 days of age. These studies show the importance of developmental stage in the response to respiratory viral infections.
Toby Crowe Lewis, M.D., M.P.H.
My research focuses on asthma epidemiology and airborne exposures.
Specific research projects include:
Interactive effects of diesel exhaust and respiratory viral infection on asthmatic children
My research team is testing the general hypothesis that traffic-associated air pollution, specifically diesel exhaust, and respiratory viral infections combine to induce exaggerated asthmatic responses in children with asthma. We are determining whether traffic-associated air pollution (Figure) increases susceptibility to viral upper respiratory tract infections, and whether combined exposures to pollutants and upper respiratory tract infections elicit augments inflammatory and oxidative stress responses, leading to worse clinical asthma outcomes.
With Dr. Marc Hershenson, my laboratory is also examining the pathogenesis of viral-induced
asthma exacerbations in children with asthma. We collect nasal aspirates before and during respiratory viral infections. We analyze the aspirates for the presence of virus and expression of host mRNAs, proteins and micro RNAs, and correlate our findings with changes in asthma symptoms and pulmonary function.
Promoting activity among children with asthma in Detroit
My research team also studies community-based health behavior interventions to improve asthma care. Children with asthma in Detroit face barriers to more active lifestyles. We currently plan a multi-faceted program to promote exercise in inner-city children with asthma which we hypothesize will improve asthma-related quality of life.
Inflammatory Effects of Post-Natal Overnutrition
Rapid post-natal growth is a risk factor for obesity and cardiometabolic disease. Using animal models we are evaluating the influence of post-natal overnutrition on innate immunity.
Funding: NIH R21 HD086696
Obesity Induced Effects on Hematopoiesis
The lab seeks to understand how obesity influences myeloid cell production from the bone marrow compartment. Funding: American Diabetes Association Career Development Award.
Antonia Popova, M.D.
The focus of my research is pulmonary complications of premature birth. These complications include bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurely-born infants in which lung alveoli fail to form normally, and asthma. My work combines animal experiments and an ex vivo lung model and, for selected studies human subject research.
My current research aims to understand the contribution of innate immune mechanisms to asthma development in prematurely born infants, especially those with BPD.
Particularly, I am studying how early-life exposures associated with premature birth, such as exposure to oxygen, bacterial endotoxins and maternal cigarette smoking during pregnancy, prime the innate immune system, causing exaggerated inflammatory responses to respiratory viral infection. Using an animal model, we found that damage associated molecular patterns, or DAMPs, activate Clec9a+CD103+ dendritic cells, thereby enhancing T cell responses to rhinovirus infection. We have also found evidence of DAMP signaling in tracheal aspirates from human preterm infants (Figure).
Funding: NIH R01 HL140572
