Regulatory roles of Osteopontin in lung epithelial inflammation and epithelial‐telocyte interaction

Abstract

BackgroundLung 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.MethodsThe 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.ResultsLevels 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.ConclusionOur 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.

Roles of glutamic pyruvate transaminase 2 in reprogramming of airway epithelial lipidomic and metabolomic profiles after smoking

“…The quality of CSE was assessed by quantifying the absorbance value at a wavelength of 320λ (1.158), as reported previously. 2 , 3 , 19 …”

“… 1 Smoking is one of the common and critical factors for the induction and development of COPD and activates the interactions amongst multiple lung cells. 1 , 2 The airway epithelial cells serve as the initial defense separating the tissue microenvironment from the external environment, the primary receptors to face and bind the pathogens, and as the secondary inducer to result in localised and systemic inflammation, pulmonary dysfunction, and tissue impairment in COPD, as a prominent characteristic of the disease. 3 , 4 , 5 In addition, lung epithelial cells play crucial roles in preserving lung function and alveolar structures and are the main source to generate potential targets for therapeutic interventions to reduce inflammation and remodelling in COPD.…”