Therapeutic characteristics of alveolar-like macrophages in mouse models of hyperoxia and LPS-induced lung inflammation.

Acute respiratory distress syndrome (ARDS) is a severe lung disease of high mortality (30-50%). Patients require lifesaving supplemental oxygen therapy; however, hyperoxia can induce pulmonary inflammation and cellular damage. Although alveolar macrophages (AMs) are essential for lung immune homeostasis, they become compromised during inflammatory lung injury. To combat this, stem cell-derived alveolar-like macrophages (ALMs) are a prospective therapeutic for lung diseases like ARDS. Using in vitro and in vivo approaches, we investigated the impact of hyperoxia on murine ALMs during acute inflammation. In vitro, ALMs retained their viability, growth, and antimicrobial abilities when cultured at 60% O₂, whereas they die at 90% O₂. In contrast, ALMs instilled in mouse lungs remained viable during exposure of mice to 90% O₂. The ability of the delivered ALMs to phagocytose Pseudomonas aeruginosa was not impaired by exposure to 60 or 90% O₂. Furthermore, ALMs remained immunologically stable in a murine model of LPS-induced lung inflammation when exposed to 60 and 90% O₂ and effectively attenuated the accumulation of CD11b⁺ inflammatory cells in the airways. These results support the potential use of ALMs in patients with ARDS receiving supplemental oxygen therapy.NEW & NOTEWORTHY The current findings support the prospective use of stem cell-derived alveolar-like macrophages (ALMs) as a therapeutic for inflammatory lung disease such as acute respiratory distress syndrome (ARDS) during supplemental oxygen therapy where lungs are exposed to high levels of oxygen. Alveolar-like macrophages directly delivered to mouse lungs were found to remain viable, immunologically stable, phagocytic toward live Pseudomonas aeruginosa, and effective in reducing CD11b⁺ inflammatory cell numbers in LPS-challenged lungs during moderate and extreme hyperoxic exposure.