RationaleSeasonal influenza A virus infection causes at least 20,000–50,000 deaths in the United States each year and causes disproportionate morbidity and mortality in older individuals. We and others have found similarly disproportionate mortality in aged mice infected with influenza A. An important role for alveolar macrophages in the response to influenza A infection is recognized. Strategies to therapeutically target alveolar macrophages during lung injury have considered that they are a single population of monocyte‐derived cells. This paradigm has been challenged by studies that identified tissue‐resident alveolar macrophages (TR‐AM) as highly specialized cells that populate the lung shortly after birth and persist over the lifespan.MethodsWe aged bone marrow chimeric C57Bl/6 (CD45.1 donor into CD45.2 host) mice generated with thoracic shielding followed by busulfan depletion of the remaining bone marrow. The resulting chimeric mice (>99% donor monocytes in blood, >99 % recipient in tissue resident alveolar macrophages), were treated with influenza A (A/WSN/33) virus, or bleomycin.ResultsSevere injury early in life alters the alveolar macrophage landscape during aging. We treated shielded‐bone‐marrow chimeric mice with influenza A or bleomycin and measured the ratio between Mo‐AM and TR‐AM 10 months later. We found that TR‐AM were remarkably stable, constituting >95% of alveolar macrophages in naïve mice at 14 months of age. In contrast, in mice infected with influenza A (A/WSN/33) virus, 100pfu at 8 weeks post bone marrow transfer (4 months of age), approximately 50% of the alveolar macrophages were monocyte‐derived 10 months later. To determine whether this finding was unique to influenza A, we treated a separate cohort of shielded‐bone‐marrow chimeric mice with bleomycin and obtained similar results. Next, we sought to determine whether the differences in gene expression between TR‐AM and Mo‐AM we observed during injury and fibrosis persisted over the lifespan. Ten months after bleomycin treatment or influenza A infection, TR‐AM and Mo‐AM were not disgtinguishable by flow cytometry. A comparison of the transcriptomes of TR‐AM and Mo‐AM 10 months after bleomycin administration revealed only 101 differentially expressed genes.ConclusionThis finding suggests that a severe injury early in life can permanently reshape the alveolar macrophage landscape with respect to its developmental origins. If monocyte‐derived alveolar macrophages differ in their response to challenge, this might explain some of the age‐related susceptibility to influenza A infection.Support or Funding InformationAG049665, HL071643, ES013995, The Veterans Administration, DOD W81XWH‐15‐1‐0215