肺上皮细胞在肺炎和损伤中发挥重要作用，尽管机制尚不清楚。骨营养素（OPN）在上皮损伤和修复以及肺癌生物学行为中起着重要作用。电泳纤维细胞（TC）是一种与上皮细胞相互作用以缓解急性炎症和肺损伤的间质细胞类型。本研究旨在探索OPN调节上皮源性肺炎症以及上皮细胞与TC在急性和慢性肺损伤中的相互作用的潜在机制。通过生物信息学定义了OPN和上皮炎症的肺病特异性。我们评估了OPN-knockdown或过度表达支气管上皮（HBE）在香烟烟雾提取物（CSE）挑战或具有基因OPN敲除（gKO）或肺部特异性OPN敲除（cKO）的动物中的调节作用。通过吸烟或脂多糖（LPS）诱导急性肺损伤和慢性阻塞性肺疾病（COPD）。使用抑制剂评估OPN对PI3K亚单位和ERK的影响。通过空间转录组学定义了OPN、OPN阳性上皮亚型和TC的分布和定位。通过共培养系统对HBE和TC之间的相互作用进行了分析。与健康非吸烟者相比，OPN表达水平在吸烟者、COPD吸烟者和COPD与肺癌吸烟者中显著增加。LPS和/或CSE导致HBE过度产生细胞因子，其依赖OPN的功能障碍。OPN-gKO或OPN-cKO小鼠的肺炎症和损伤严重程度显著降低。转导OPN的HBE增强了磷脂酰肌醇3激酶（PI3K）CA/p110α、PIK3CB/p110β、PIK3CD/p110δ、PIK3CG/p110γ、PIK3R1、PIK3R2或PIK3R3的表达。OPN和OPN阳性上皮亚型的空间位置显示了气道上皮和TC的紧密接触。上皮OPN调节了上皮与TC的相互交流，而OPN的下调在转录组谱中引起的改变明显多于上调。我们的数据证明了OPN在急性和慢性肺损伤中调节肺上皮炎症、损伤和细胞交流的作用。条件控制肺上皮OPN可能是预防和治疗上皮源性肺炎症和损伤的一种替代方法。© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.

Lung epithelial cells play important roles in lung inflammation and injury, although mechanisms remain unclear. Osteopontin (OPN) has essential roles in epithelial damage and repair and in lung cancer biological behaviours. Telocyte (TC) is a type of interstitial cell that interacts with epithelial cells to alleviate acute inflammation and lung injury. The present studies aim at exploring potential mechanisms by which OPN regulates the epithelial origin lung inflammation and the interaction of epithelial cells with TCs in acute and chronic lung injury.The lung disease specificity of OPN and epithelial inflammation were defined by bioinformatics. We evaluated the regulatory roles of OPN in OPN-knockdown or over-expressed bronchial epithelia (HBEs) challenged with cigarette smoke extracts (CSE) or in animals with genome OPN knockout (gKO) or lung conditional OPN knockout (cKO). Acute lung injury and chronic obstructive pulmonary disease (COPD) were induced by smoking or lipopolysaccharide (LPS). Effects of OPN on PI3K subunits and ERK were assessed using the inhibitors. Spatialization and distribution of OPN, OPN-positive epithelial subtypes, and TCs were defined by spatial transcriptomics. The interaction between HBEs and TCs was assayed by the co-culture system.Levels of OPN expression increased in smokers, smokers with COPD, and smokers with COPD and lung cancer, as compared with healthy nonsmokers. LPS and/or CSE induced over-production of cytokines from HBEs, dependent upon the dysfunction of OPN. The severity of lung inflammation and injury was significantly lower in OPN-gKO or OPN-cKO mice. HBEs transferred with OPN enhanced the expression of phosphoinositide 3-kinase (PI3K)CA/p110α, PIK3CB/p110β, PIK3CD/p110δ, PIK3CG/p110γ, PIK3R1, PIK3R2 or PIK3R3. Spatial locations of OPN and OPN-positive epithelial subtypes showed the tight contact of airway epithelia and TCs. Epithelial OPN regulated the epithelial communication with TCs, and the down-regulation of OPN induced more alterations in transcriptomic profiles than the up-regulation.Our data evidenced that OPN regulated lung epithelial inflammation, injury, and cell communication between epithelium and TCs in acute and chronic lung injury. The conditional control of lung epithelial OPN may be an alternative for preventing and treating epithelial-origin lung inflammation and injury.© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.