The focus of our laboratory is on 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.
Bronchopulmonary dysplasia (BPD) is a chronic lung disease of prematurely-born infants in which lung alveoli fail to form normally. Survivors of prematurity, especially those with BPD develop asthma later in life. We investigate the cellular and molecular innate immune mechanisms that are activated and primed by exposures associated with preterm birth (e.g. hyperoxia or infection) and contribute to BPD and asthma development. Our approach combines animal and in vitro experiments, and, in selected studies, human subjects research. Our goal is to uncover novel innate immune pathways responsible for long-term lung disease in prematurely born infants and identify new targets for therapeutic intervention. Current projects focus on:
Effects of early-life exposure to hyperoxia on lung innate immune responses and the development of BPD and asthma. We are investigating the mechanisms by which neonatal hyperoxia primes the pulmonary innate immune system and leads to enhanced inflammatory responses to respiratory viral infections. Since hyperoxia induces lung cell necrosis, we focus on necrotic cells exposed F-actin, a damage-associated molecular pattern (DAMP) which through its binding to Clec9a, a DAMP receptor on lung CD103+ DCs induces their activation. We are exploring the mechanisms of this priming effect and its contribution to exaggerated pro-inflammatory responses to future TLR3 stimulation.
Role of infection and inflammation on impaired lung alveolar growth. Since inflammation and infection, have been associated with BPD development, we have developed a novel mouse model of BPD by inoculating immature mice with lipopolysaccharide (LPS), an immunogenic gram-negative bacterial wall component. Chronic neonatal LPS exposure induces inflammation and disrupts alveolar growth leading to fewer and larger alveolar spaces, reminiscent of human BPD. We are investigating the contribution of non-conventional T cells and innate lymphocytes, and specifically their cell stress receptor NKG2D in chronic neonatal LPS-induced pulmonary inflammation and hypoalveolarization.