Isoalantolactone Attenuates LPS-Induced Acute Lung Injury, an Effect Associated with Suppressed MAPK/STAT3 Activation and Epithelial-Mesenchymal Transition

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Background: Acute lung injury (ALI) is characterized by a high mortality rates and acute inflammation that compromises the epithelial and endothelial barriers of the respiratory system.Isoalantolactone (IsoA) is a natural compound derived from Inula helenium that has been shown to exhibit anti-inflammatory activity.However, its ability to preserve epithelial barrier integrity or modulate mitogen-activated protein kinase/signal transducer and activator of transcription 3 (MAPK/STAT3) signaling and epithelial-mesenchymal transition (EMT) has not been evaluated in ALI.Methods: Human bronchial epithelial cells (HBEC3-KT and BEAS-2B) were stimulated with lipopolysaccharide (LPS) with or without IsoA to assess cytotoxicity and cytokine release.In vivo, female C57BL/6 mice were pretreated with IsoA (10-20 mg/kg, intraperitoneally) or vehicle 1 h before LPS challenge (1 mg/kg, intratracheally).At 4 h, lung tissues and bronchoalveolar lavage fluid (BALF) were collected for histopathology and to measure total protein, cellular composition, and cytokine levels (tumor necrosis factorα [TNF-α], interleukin-6 [IL-6], monocyte chemoattractant protein-1 [MCP-1]); leukocyte subsets were quantified by multicolor flow cytometry.Lung homogenates were analyzed using Western blot for phosphorylated/total extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase 1/2 (JNK1/2), p38 MAPKs, STAT3, and EMT markers (E-cadherin, N-cadherin, snail).Results: In LPS-stimulated HBEC3-KT and BEAS-2B cells, IsoA significantly reduced IL-6 secretion.In the murine model of LPS-induced ALI, IsoA administration alleviated lung tissue damage, decreased inflammatory cell infiltration, and reduced IL-6 and TNF-α concentration in BALF and serum.Mechanistically, IsoA attenuated the phosphorylation of ERK, JNK, and p38 MAPKs and suppressed STAT3 activation in lung tissues.Furthermore, IsoA attenuated EMT, as evidenced by decreased N-cadherin and snail expressions and restored E-cadherin expression.Conclusions: IsoA alleviates LPS-induced ALI by reducing MAPK/STAT3 activation and EMT-associated epithelial injury.These findings suggest that IsoA may be a promising candidate for the targeted modulation of inflammatory lung injury, and that further preclinical and translational studies are justified.

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