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Alveolar macrophages inhibit emphysematous pathology via expression of carbonic anhydrase 4.

ABSTRACT: Chronic obstructive pulmonary disease (CODP) including emphysema affects approximately 400 million individuals worldwide. Therapies to treat COPD remain limited and fail to prevent disease progression. Alveolar macrophages (AMs) reside in the alveoli of the lung and are ideally positioned to encounter inhaled particles and pathogens. Despite exposure to these stimuli, AMs exhibit specialized phenotypes that restrict inflammation to prevent alveolar damage. Here we demonstrate that AMs express high levels of the surface bound enzyme carbonic anhydrase 4 (Car4). Deletion of Car4 on AMs results in increased susceptibility to emphysematous pathology and therapeutic treatment with Car4 is sufficient to prevent emphysema-like disease. Consistent with our murine studies, reduced levels of Carbonic anhydrase 4 (CAIV) distinguishes COPD patients with emphysema from those without emphysema. Mechanistically, murine and human Car4 directly inhibit elastase that promotes destruction of alveolar walls. Collectively, these studies reveal an underappreciated function for Car4 in preventing lung pathology.

ORGANISM(S): Mus musculus

PROVIDER: GSE298037 | GEO | 2026/03/23

REPOSITORIES: GEO

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	GSE298037_merged_gene_counts.txt.gz	Txt

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Project description:Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how microRNA expression is altered with regional emphysema severity within the lung and how these microRNAs regulate disease-associated gene-expression networks. Results: We profiled microRNAs in different regions in the lung with varying degrees of emphysema from 6 smokers with COPD and 2 controls (8 regions x 8 lungs = 64 samples). 63 microRNAs (p<0.05) were altered with regional emphysema severity as quantified by mean linear intercept (Lm). MicroRNA and gene expression data were then integrated in the same samples. A subset of microRNAs, including miR-638, miR-30c, and miR-181d, correlated with many of their predicted gene targets, suggesting a role in regulating the gene networks that underlie emphysematous lung destruction. Modulating miR-638 expression in primary human lung fibroblasts recapitulated the alterations in its targeted gene-expression network associated with emphysema progression. Pathway analysis revealed that genes involved in oxidative stress and accelerated aging were affected by miR-638 knock-down in fibroblasts. Many miR-638 gene targets in these pathways were amongst those negatively correlated with miR-638 expression in emphysematous lung tissue. Conclusions: Our findings demonstrate that microRNAs are altered with regional emphysema severity and modulate disease-associated gene expression networks. Furthermore, miR-638 may regulate gene expression associated with the oxidative stress response and aging in emphysematous lung tissue and fibroblasts. Paired samples were obtained from 8 regions at regular intervals between the apex and base of each explanted lung from six patients with severe COPD and two donors. The degree of emphysematous destruction was quantified in one sample from each region by mean linear intercept (Lm), while microRNA expression was profiled in the adjacent sample from the same region using the NCode Version 3 microRNA microarrays (Invitrogen, Carlsbad, CA). After quality control 60 samples were used for the analysis.

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Alveolar macrophages inhibit emphysematous pathology via expression of carbonic anhydrase 4.

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