Background: Bronchopulmonary dysplasia (BPD) and pulmonary hypertension associated with BPD (BPD-PH) are severe cardiopulmonary morbidities faced by the preterm infant. These diseases are multifactorial in origin and underpinned by a rise in pulmonary inflammation. As there are no targeted anti-inflammatory therapies available there remains a major unmet need. Most rodent models of BPD induce disease with only postnatal hyperoxia, mimicking the increased fraction of inspired oxygen (FiO2) often required in preterm infants. However, antenatal inflammation is a major driver of preterm birth and subsequent early life cardiopulmonary disease pathophysiology. Method: To account for the multifactorial origins of early life cardiopulmonary disease, we established a double hit model, combining antenatal systemic inflammation followed by postnatal hyperoxia. On embryonic day 14, pups are exposed to systemic maternal inflammation via a single intraperitoneal injection of 150 µg/kg of lipopolysaccharide to the dam. Within 24 h after birth, pups, and dams are randomized and exposed to gas with either an FiO2 of 0.21 (room air) or 0.65 (hyperoxia 65%) for 28 days. Results: The combination of antenatal LPS and postnatal hyperoxia causes substantial damage to pulmonary architecture, including the development of large dysmorphic alveoli and a reduction in the number of small blood vessels. These clinically relevant structural changes translate to impaired gas exchange, increased pulmonary vascular resistance, and increased pulmonary blood pressure like what can be observed in BPD and BPD-PH. Conclusions: We developed a clinically relevant murine model of disease by combining two key inciting stimuli to accurately reflect the multifactorial pathogenesis of human early life cardiopulmonary disease. The disease severity induced by the murine double hit model is ameliorated by (1) the administration of daily low dose anakinra (recombinant IL-1 receptor antagonist) to wildtype mice or (2) the use of mice deficient in the central transducer of type 2 signalling (STAT6). Thereby establishing IL-1 and type 2 immune responses crucial in murine BPD and BPD-PH.