A new study has found that cigarette smoke exposure activates a proinflammatory phenotype of alpha-1 antitrypsin deficiency (AATD) macrophages.

The study, published in Respiratory Research, also found that extracellular vesicles induced by cigarette smoke release higher levels of the mutant Z variant of alpha-1 antitrypsin (ATT), known as ZAAT, which could exacerbate lung disease in patients with AATD.

“We have previously shown that peripheral blood monocyte-derived macrophages from AATD individuals have impaired efferocytosis and dysregulated proteolytic activity. Taken together, these data suggest an altered phenotype of AATD macrophages could be involved in the pathogenesis and severity of AATD-mediated [chronic obstructive pulmonary disease],” the authors wrote.

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“We therefore hypothesized that enhanced inflammatory phenotype of AATD macrophages and dysregulated response to cigarette smoke and cigarette smoke-induced [extracellular vesicles] contribute to the development of lung inflammation in AATD individuals.”

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The research team obtained peripheral blood mononuclear cells from healthy individuals and patients with AATD, cultured them, and exposed them to air or cigarette smoke. They quantified cytokine secretion and endoplasmic reticulum stress using quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA). Lastly, they exposed the macrophages to extracellular vesicles released by airway epithelial cells exposed to cigarette smoke and measured their inflammatory response.

The results showed that, when exposed to cigarette smoke-induced extracellular vesicles released by airway epithelial cells, AATD macrophages had an enhanced inflammatory response. This response exceeded the already proinflammatory nature of AATD macrophages compared with that of normal macrophages.

Furthermore, cigarette smoke-induced extracellular vesicles had no effect on normal macrophages but led to granulocyte macrophage-colony stimulating factor and interleukin 8 expression in AATD macrophages.

The authors hope these results will deepen the understanding of the mechanisms underlying the effect of AATD on lung tissue and lead to the identification of a new strategy to control the enhanced macrophage response to cigarette smoke in patients with AATD and lung inflammation.


Khodayari N, Oshins R, Mehrad, B, et al. Cigarette smoke exposed airway epithelial cell-derived EVs promote pro-inflammatory macrophage activation in alpha-1 antitrypsin deficiency. Respir Res. 2022;23(1):232. doi:10.1186/s12931-022-02161-z