Continuous crosstalk between alveolar macrophages (AMs) and the alveolar epithelium is essential to maintaining alveolar health and becomes particularly important in regeneration after injury. While cellular iron loading in AMs has clearly been characterized in chronic obstructive pulmonary disease (COPD), little is known about whether these iron-loaded AMs contribute to alveolar type 2 epithelial cell (AEC2) dysfunction, impaired regenerative capacity, and emphysema development in COPD pathophysiology. This study aimed to determine whether iron-loaded AMs impair AEC2 function through irregular crosstalk in an in vitro model of COPD. Foetal liver-derived AMs were iron-loaded in vitro by treatment with 53 ng/ml ferric ammonium citrate, 10 ?M ferrous lactate, or 5% cigarette smoke extract for 24h. MLE-12 cells were incubated with conditioned medium (CM) of AMs for 24h and changes in MLE-12 viability, surfactant handling, and cellular iron metabolism were assessed by alamarBlue assay, immunoblotting, and RT-qPCR. Cellular iron was measured by atomic absorption spectroscopy. MLE-12 wound healing capacity was assessed by scratch assay. CM of iron-loaded AMs did not significantly affect MLE-12 viability but lead to significant iron accumulation in MLE-12s. MLE-12s treated with CM of iron-loaded AMs showed significantly reduced expression of pro-Surfactant Protein C but no change in the production or uptake of surfactant lipids. CM of iron-loaded AMs altered MLE-12 wound healing capacity. While AM-AEC2 crosstalk is essential for regeneration after injury, dysregulated crosstalk between iron-loaded AMs and AEC2s may contribute to COPD pathophysiology by inducing AEC2 dysfunction and tissue damage.