Farnesoid X receptor regulates lung macrophage activation and injury following nitrogen mustard exposure

Toxicol Appl Pharmacol. 2022 Nov 1:454:116208. doi: 10.1016/j.taap.2022.116208. Epub 2022 Aug 23.


Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis; this is associated with a sequential accumulation of pro- and anti-inflammatory macrophages in the lung which have been implicated in NM toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating lipid homeostasis and inflammation. In these studies, we analyzed the role of FXR in inflammatory macrophage activation, lung injury and oxidative stress following NM exposure. Wild-type (WT) and FXR-/- mice were treated intratracheally with PBS (control) or NM (0.08 mg/kg). Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 3, 14 and 28 d later. NM caused progressive histopathologic alterations in the lung including inflammatory cell infiltration and alveolar wall thickening and increases in protein and cells in BAL; oxidative stress was also noted, as reflected by upregulation of heme oxygenase-1. These changes were more prominent in male FXR-/- mice. Flow cytometric analysis revealed that loss of FXR resulted in increases in proinflammatory macrophages at 3 d post NM; this correlated with upregulation of COX-2 and ARL11, markers of macrophage activation. Markers of anti-inflammatory macrophage activation, CD163 and STAT6, were also upregulated after NM; this response was exacerbated in FXR-/- mice at 14 d post-NM. These findings demonstrate that FXR plays a role in limiting macrophage inflammatory responses important in lung injury and oxidative stress. Maintaining or enhancing FXR function may represent a useful strategy in the development of countermeasures to treat mustard lung toxicity.

Keywords: FXR; Lung toxicity; Macrophages; Mustard vesicants; Oxidative stress.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Lung Injury* / pathology
  • Animals
  • Cyclooxygenase 2 / metabolism
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism
  • Irritants / toxicity
  • Lipids
  • Lung
  • Macrophage Activation
  • Male
  • Mechlorethamine* / toxicity
  • Mice


  • Irritants
  • Lipids
  • Mechlorethamine
  • Heme Oxygenase-1
  • Cyclooxygenase 2