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  • Mt a known to be upregulated by


    Mt2a, known to be upregulated by ozone (Inoue et al., 2008), was also increased in vehicle-pretreated rats exposed to ozone, however, this effect was markedly reduced by both PROP and MIFE, suggesting that the neuroendocrine response is linked to ozone-induced acute phase protein expression. In humans, Mt2a gene transcription is activated by GR activation (Sato et al., 2013) and in a murine restrained stress model, Mt2a expression correlated with increased corticosterone levels (Jacob et al., 1999). This observation is in agreement with previous work from our lab showing that the removal of adrenal glands – which is the source of both epinephrine and corticosterone – reduced the ozone-induced up-regulation of Mt2a and many other acute phase response genes (Henriquez et al., 2017). The increased expression of the glucocorticoid-responsive gene Tsc22d3 after ozone exposure supports the corticosterone-mediated activation of GR in the lungs. In conclusion, by blocking βAR and GR activity using PROP and MIFE pretreatments, respectively, we selectively minimized ozone-induced lung protein leakage, macrophage activation, neutrophilic inflammation, lymphopenia, and pulmonary inflammatory cytokine expression in rats (Fig. 8). These findings suggest a significant mechanistic role of ozone-induced increases in circulating stress hormones, the activation of βAR and GR, and the possible downstream effects on cell signaling through these receptors that result in lung injury and inflammation. Moreover, since βAR and GR agonists are commonly used in the treatment of chronic inflammatory conditions of the lung, including Ozagrel synthesis and chronic obstructive pulmonary disease, those receiving such treatments may show differential susceptibility to air pollution-induced lung effects.
    Conflict of interest
    Acknowledgements The authors would like to thank Drs. Aimen Farraj, Stephen Gavett, Wayne Cascio and Ian Gilmour of the US EPA for their critical review of the manuscript, and Ms. Cynthia Fisher for her help in the mRNA PCR experiment. We acknowledge the help of Dr. Mark Higuchi in performing inhalation exposures and Mr. Abdul Malek Khan in operating ozone exposure chambers. This work was supported in part by Fulbright (Becas Chile, CONICYT; IIE-15120279) to A.H. and the EPA-UNC Center for Environmental Medicine, Asthma and Lung Biology Cooperative Agreement (CR-83515201) as well as EPA-UNC Cooperative Training Agreement (CR-83578501).
    Introduction The major component of microtubules (MTs) is the heterodimeric protein tubulin. Numerous proteins are known to interact with tubulin and regulate MT assembly either by promoting the polymerization of tubulin or by stabilizing MTs. These proteins are collectively known as microtubule-associated proteins (MAPs). Members of this group of proteins, such as MAP2 and tau, are known to promote MT assembly and stabilize MTs in vivo and in vitro [1,2]. Several other proteins, including Op18/stathmin, katanin, and some kinesin-related motor proteins, act on MTs by destabilizing the polymer [[3], [4], [5]]. Although these studies identified and characterized the cellular factors that regulate MT assembly and dynamics, the precise spatial and temporal control of the process has not been clearly understood. Heterotrimeric G proteins play an important role in transferring signals from cell surface receptors (G protein-coupled receptors, GPCRs) to intracellular effector molecules. G protein heterotrimer, consisting of guanine nucleotide binding α plus βγ subunits, is inactive in cellular signaling. Agonist binding to GPCRs triggers structural rearrangements in the receptors such that the intracellular domain then catalyzes a nucleotide exchange in the α subunit of heterotrimeric G proteins. Subsequently, activated Gα changes its association with Gβγ in a manner that permits both subunits to participate in the regulation of intracellular effector molecules [[6], [7], [8]]. Although G proteins are likely to be membrane-bound when coupled to receptors, recent results from various laboratories suggest that G proteins associate with MTs, and regulate assembly/dynamics of MTs [reviewed in 9, 10]. It has been shown that α subunits of G proteins (Gsα, Gi1α and Gqα) inhibit MT assembly and promote MT dynamics in vitro [11]. In contrast, Gβγ promotes MT assembly [12]. Also, reconstituted Gαβγ heterotrimers were found to be inactive in the modulating MT assembly [13], suggesting that receptor-mediated activation of G proteins may involve modulation of MT assembly by G proteins.