LncRNA CDKN2B‐AS1 interacts with LIN28B to exacerbate sepsis‐induced acute lung injury by inducing HIF‐1α/NLRP3‐mediated pyroptosis

Abstract

Abstract Sepsis‐associated acute lung injury (ALI) is a life‐threatening condition in intensive care units with high mortality. LncRNAs have been confirmed to participate in the underlying pathogenesis of septic ALI. This study investigated the biological functions of lncRNA CDKN2B‐AS1 in septic ALI and its potential mechanism.BEAS‐2B cells were challenged with lipopolysaccharide (LPS) and mice were subjected to caecal ligation and puncture (CLP) to induce septic ALI in vitro and in vivo. The expression levels of CDKN2B‐AS1, LIN28B, HIF‐1α, and pyroptosis‐related molecules were assessed by qRT–PCR or Western blotting. The production of IL‐1β and IL‐18 was detected by ELISA. BEAS‐2B cell pyroptosis was examined by flow cytometry. The interaction between LIN28B and CDKN2B‐AS1/HIF‐1α was validated by RIP and RNA pull‐down assays. Colocalization of CDKN2B‐AS1 and LIN28B was observed by FISH. ALI was determined by HE staining, the lung wet‐to‐dry (W/D) weight ratio, inflammatory cell numbers, and total protein concentration in bronchoalveolar lavage fluid (BALF). Caspase‐1 expression in the lung tissues was examined by immunohistochemical staining.CDKN2B‐AS1 was upregulated in BEAS‐2B cells after LPS stimulation. CDKN2B‐AS1 knockdown inhibited pyroptosis in LPS‐exposed BEAS‐2B cells in vitro and the lung tissues of septic mice in vivo. Mechanistically, CDKN2B‐AS1 interacted with LIN28B to enhance HIF‐1α stability. Rescue experiments showed that HIF‐1α overexpression counteracted the inhibitory effect of sh‐CDKN2B‐AS1 on LPS‐induced pyroptosis. CDKN2B‐AS1 bound to LIN28B to trigger NLRP3‐mediated pyroptosis by stabilizing HIF‐1α, which promoted sepsis‐induced ALI. CDKN2B‐AS1 might be a novel therapeutic target for this disease.

Keywords

• CDKN2B‐AS1
• HIF‐1α
• LIN28B
• pyroptosis
• Sepsis‐induced acute lung injury