Instructor of Pediatrics Harvard Medical School Jamaica Plain, Massachusetts, United States
Background: Bronchopulmonary dysplasia (BPD) is a significant cause of morbidity in preterm infants, including long-term pulmonary complications such as an increased risk for respiratory viral infections and asthma. There is limited understanding regarding the pathogenesis of long-term BPD pulmonary complications, however, there have been some links with immune dysfunction in preclinical studies. We hypothesize that neonatal hyperoxia (HYRX) injury results in immune dysfunction that exacerbates an asthma phenotype later in life. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have demonstrated immunomodulatory effects and protection from perinatal injury in multiple preclinical models of neonatal disease including BPD but their long term protective effects require further study. Objective: Using a double hit murine model of HYRX followed by allergic asthma induced with house dust mite (HDM) treatment (HYRX HDM) to evaluate if HYRX exposure results in long-term immunologic dysfunction and evaluate the effect of MSC-EVs on this process. Design/Methods: Neonatal FVB mice were exposed to HYRX (75% O2) from postnatal day 0 (PN0) to PN7 followed by recovery in normoxia until PN14, after which they were treated with HDM intranasally for 2 weeks. At PN3, MSC-EVs were injected intravenously via the superficial temporal vein. At PN28, lungs were evaluated histologically for evidence of inflammation and goblet cell hyperplasia. Animals underwent pulmonary function tests and methacholine challenge to evaluate the severity of the asthma phenotype. Bronchoalveolar lavage fluid was harvested to assess cytokine concentrations and cellular composition. Results: The HYRX HDM animals demonstrated increased mucin deposition and airway hyper-responsiveness compared to asthma controls. HYRX HDM animals generated increased type 2 cytokines (IL-4, IL-5, IL-13) accompanied by increased lymphocytic infiltration of the airways compared to asthma controls, which was attenuated by MSC-EV treatment. Resident alveolar macrophages (AMs) from HYRX animals revealed an activated phenotype characterized by increased granularity, SiglecFlo and CD206hi expression and retained their altered phenotype ex vivo demonstrating an increased pro-inflammatory response to HDM challenge.
Conclusion(s): We demonstrated that HYRX exaggerates the inflammation, mucin production and airway hyper-reactivity of the asthma phenotype and that MSC-EV treatment can attenuate the increased airway inflammation. Finally, we established in ex vivo studies that HYRX modulates the phenotype and functionality of AMs suggestive of long-term immune dysregulation.
