RT Journal Article
SR Electronic
T1 Intratracheal Administration of Acat-1 Inhibitor K-604 Reduces Pulmonary Inflammation Following Bleomycin-induced Lung Injury
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP JPET-AR-2022-001284
DO 10.1124/jpet.122.001284
A1 Emily R Stevenson
A1 Melissa L Wilkinson
A1 Elena Abramova
A1 Changjiang Guo
A1 Andrew J Gow
YR 2022
UL http://jpet.aspetjournals.org/content/early/2022/08/13/jpet.122.001284.abstract
AB Acute lung injury (ALI) is characterized by epithelial damage, barrier dysfunction, and pulmonary edema. Macrophage activation and failure to resolve play a role in ALI, thus macrophage phenotype modulation is a rational target for therapeutic intervention. Large, lipid-laden macrophages have been observed in various injury models, including intratracheal bleomycin (ITB), suggesting that lipid storage may play a role in ALI severity. The endoplasmic reticulum-associated enzyme Acat-1 (Soat1) is highly expressed in macrophages where it catalyzes the esterification of cholesterol, leading to intracellular lipid accumulation. We hypothesize that inhibition of Acat-1 will reduce macrophage activation and improve outcomes of lung injury in ITB. K-604, a selective inhibitor of Acat-1, was used to reduce cholesterol esterification and hence lipid accumulation in response to ITB. Male and female C57BL6/J mice (n=16-21/group) were administered control, control + K-604, ITB, or ITB + K-604 on d0, control or K-604 on d3, and were sacrificed on d7. ITB caused significant body weight loss and an increase in cholesterol accumulation in BAL cells. These changes were mitigated by Acat-1 inhibition. K-604 also significantly reduced ITB-induced alveolar thickening. Surfactant composition was normalized as indicated by a significant decrease in phospholipid:SP-B ratio in ITB+K-604 compared to ITB. K-604 administration preserved mature alveolar macrophages, decreased activation in response to ITB, and decreased the percentage mature and pro-fibrotic interstitial macrophages. These results show that inhibition of Acat-1 in the lung is associated with reduced inflammatory response to ITB-mediated lung injury. Significance Statement Acat-1 is critical to lipid droplet formation, and thus Inhibition of Acat-1 thus presents as a pharmacological target. Intratracheal administration of K-604, an Acat-1 inhibitor, reduces intracellular cholesterol ester accumulation in lung macrophages, attenuates inflammation and macrophage activation, and normalizes mediators of surface-active function after intratracheal bleomycin administration in a rodent model. The data presented within suggest that inhibition of Acat-1 in the lung improves acute lung injury outcomes.