The Role And Mechanism Of Formaldehyde Exposure In The Development Of Airway Inflammation And Bronchial Hyperresponsiveness

?Objective?Asthma is a common chronic respiratory disease characterized by airway inflammation and bronchial hyperresponsiveness in children.Over the last several decades,the prevalence of asthma has dramatically increased among children in our country.Epidemiological evidence suggests that this rapid increase in prevalence is mainly due to exposure to indoor pollutants such as formaldehyde(FA).However,the role and mechanism of FA exposure in the development and severity of allergic asthma is still poorly understood.?Methods?(1)Both Balb/c and C57bl/6 mice were randomly divided into two main groups:thenon-sensitized group and the sensitized group.Both non-sensitized and sensitizedmice were exposed to three concentrations of FA(0,0.5 and 3.0 mg/m~3),for 6 h/dayover 25 consecutive days.24 h after the final FA exposure,airway inflammation wasevaluated by inflammatory cell counts in bronchoalveolar lavage fluid(BALF),andbronchial responsiveness to methacholine was measured by the Ani Res 2005 LungFunction system.The concentrations of T helper(Th)cytokines in BALF andOVA-specific immunoglobulin in serum were measured by by enzyme-linkedimmunosorbent assay(ELISA).(2)High-throughput sequencing was used to investigate potential changes in mRNAs andlncRNAs expression profiles induced by FA exposure in human cultured airwaysmooth muscle cells.For ectopic expression of mRNAs,GO and pathway enrichmentanalysis were performed by bioinformatics methods.In addition,the m RNA-lnc RNA-network was constructed based on the correlation analysis between thedifferential expressed mRNAs and lncRNAs.?Results?(1)In non-sensitized group,exposure to 0.5 mg/m~3 and 3.0 mg/m~3 FA significantlyincreased the production of Th2 cytokines(IL-4,IL-5 and IL-13),eosinophilicinflitration and airway inspiratory and expiratory resistance in both Balb/c and C57blmice.(2)Inhalation of 0.5 mg/m~3 FA in sensitized C57BL/6 mice resulted in exacerbatedOVA-induced allergic responses,and exposure to 3.0 mg/m~3 FA during sensitizationled to the suppression of allergic reactions in sensitized C57BL/6 mice.By contrast,exposure to 0.5 mg/m~3or 3.0 mg/m~3FA in sensitized BALB/c mice suppressed thedevelopment of OVA-induced allergic responses.(3)Balb/c mice exposed to 3.0 mg/m~3 FA had much higher IL-4,IL-5 and IL-13 levelsand eosinophil counts in the BALF than that of C57bl/6 mice.In addition,exposure ofBalb/c mice to 3.0 mg/m~3 FA induced a markedly increased expiratory resistance thatwas much greater than the increase in C57bl/6 mice.(4)FA exposure significantly disrupted the expression levels of 556 mRNAs and 354lncRNAs.Of the 556 mRNAs,168 were significantly increased and 388 weresignificantly decreased in expression.Of the 354 lncRNAs,127 were significantlyincreased and 227 were significantly decreased in expression.(5)GO and pathway enrichment analysis indicated that differentially expressed mRNAswere correlated with activation of innate immune response,inflammatory response,cell chemotaxis,histone acetylation,nitric oxide biosynthetic process,reactive oxygenspecies metabolic process,and regulation of autophagy,and also involved inimmune-related pathways,such as Toll-like recepor signialing pathway,TGF-?signialing pathway,Fc?RI signialing pathway,NF-??signialing pathway and so on.(6)The m RNA-lnc RNA-network indicated that lnc RNA MIR22HG was significantlyincreased in expression,which was located at the core of the co-expression network,and correlated with mRNAs,such as TGFBR3,SGK1,SSH2,FLRT3,ETS2,HSPA1B,KIAA0355 and so on.?Conclusions?(1)In non-sensitized group,exposure to FA could induce the development of airwayinflammation and bronchial hyperresponsiveness in both Balb/c and C57bl mice.InOVA-sensitized group,exposure to FA during sensitization could induce differentimmunoenhancing or immunosuppressed responses between Balb/c and C57bl mice.(2)Balb/c and C57bl mice had markedly different susceptibility to FA and thus differentimmune responses to FA.FA-induced allergic responses were significantly moreprominent in Balb/c mice than in C57bl/6 mice.(3)The differential expressed mRNAs and lncRNAs identified by microarray analysis areclosely related to the biological characteristics of asthma.FA may induce airwayinflammation and airway hyperresponsiveness by regulating the expression of thesemRNAs and lncRNAs.