Chanèle Cyr-Depauw1,2, Maria Hurskainen1,2, Arul Vadivel1,2, Ivana Mižíková1,2, Flore Lesage1,2, Bernard Thébaud3,4,5. 1. Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada. 2. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada. 3. Sinclair Centre for Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, ON, Canada. bthebaud@ohri.ca. 4. Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada. bthebaud@ohri.ca. 5. Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada. bthebaud@ohri.ca.
Abstract
BACKGROUND: Bronchopulmonary dysplasia (BPD), the most common complication of prematurity, arises from various factors that compromise lung development, including oxygen and inflammation. Hyperoxia has been used to mimic the disease in newborn rodents. The use of a second hit to induce systemic inflammation has been suggested as an added strategy to better mimic the inflammatory aspect of BPD. Here we report a novel 2 hit (2HIT) BPD model with in-depth characterization of the innate immune response, enabling mechanistic studies of therapies with an immunomodulatory component. METHODS: C57BL/6N mice were exposed to 85% O2 from postnatal day (P)1 to P7, and received postnatally (P3) Escherichia coli LPS. At various timepoints, immune activation in the lung and at the systemic level was analyzed by fluorescence-activated cell sorting (FACS), and gene and protein expressions. RESULTS: 2HIT mice showed fewer alveoli, increased lung compliance, and right ventricular hypertrophy. A transient proinflammatory cytokine response was observed locally and systemically. Type 2 anti-inflammatory cytokine expression was decreased in the lung together with the number of mature alveolar macrophages. Simultaneously, a Siglec-F intermediate macrophage population emerged. CONCLUSION: This study provides long-term analysis of the 2HIT model, suggesting impairment of type 2 cytokine environment and altered alveolar macrophage profile in the lung. IMPACT: We have developed a novel 2HIT mouse BPD model with postnatal LPS and hyperoxia exposure, which enables mechanistic studies of potential therapeutic strategies with an immunomodulatory component. This is the first report of in-depth characterization of the lung injury and recovery describing the evolution of the innate immune response in a standardized mouse model for experimental BPD with postnatal LPS and hyperoxia exposure. The 2HIT model has the potential to help understand the link between inflammation and impaired lung development, and will enable testing of new therapies in a short and more robust manner.
BACKGROUND: Bronchopulmonary dysplasia (BPD), the most common complication of prematurity, arises from various factors that compromise lung development, including oxygen and inflammation. Hyperoxia has been used to mimic the disease in newborn rodents. The use of a second hit to induce systemic inflammation has been suggested as an added strategy to better mimic the inflammatory aspect of BPD. Here we report a novel 2 hit (2HIT) BPD model with in-depth characterization of the innate immune response, enabling mechanistic studies of therapies with an immunomodulatory component. METHODS: C57BL/6N mice were exposed to 85% O2 from postnatal day (P)1 to P7, and received postnatally (P3) Escherichia coli LPS. At various timepoints, immune activation in the lung and at the systemic level was analyzed by fluorescence-activated cell sorting (FACS), and gene and protein expressions. RESULTS: 2HIT mice showed fewer alveoli, increased lung compliance, and right ventricular hypertrophy. A transient proinflammatory cytokine response was observed locally and systemically. Type 2 anti-inflammatory cytokine expression was decreased in the lung together with the number of mature alveolar macrophages. Simultaneously, a Siglec-F intermediate macrophage population emerged. CONCLUSION: This study provides long-term analysis of the 2HIT model, suggesting impairment of type 2 cytokine environment and altered alveolar macrophage profile in the lung. IMPACT: We have developed a novel 2HIT mouse BPD model with postnatal LPS and hyperoxia exposure, which enables mechanistic studies of potential therapeutic strategies with an immunomodulatory component. This is the first report of in-depth characterization of the lung injury and recovery describing the evolution of the innate immune response in a standardized mouse model for experimental BPD with postnatal LPS and hyperoxia exposure. The 2HIT model has the potential to help understand the link between inflammation and impaired lung development, and will enable testing of new therapies in a short and more robust manner.
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