Access to self-care interventions can improve health outcomes for people experiencing homelessness
Authors: Jonathan Hopkins, Manjulaa Narasimhan
Journal: BMJ (2022)

Up-regulation of vascular cell adhesion molecule-1 (VCAM-1) involves adhesions between both circulating and resident leukocytes and the human tracheal smooth muscle cells (HTSMCs) during airway inflammatory reaction. We have demonstrated previously that tumor necrosis factor (TNF)-α-induced VCAM-1 expression is regulated by mitogen-activated protein kinases, nuclear factor-κB, and p300 activation in HTSMCs. In addition to this pathway, phosphorylation of Akt and CaM kinase II has been implicated in histone acetyltransferase and histone deacetylase 4 (HDAC4) activation. Here, we investigated whether these different mechanisms participated in TNF-α-induced VCAM-1 expression and enhanced neutrophil adhesion. TNF-α significantly increased HTSMC-neutrophil adhesions, and this effect was associated with increased expression of VCAM-1 on the HTSMCs and was blocked by the selective inhibitors of Src [4-amino-5-(4-methylphenyl)-7-(<i>t</i>-butyl)pyrazolo[3,4-<i>d</i>]-pyrimidine (PP1)], epidermal growth factor receptor [EGFR; 4-(3′-chloroanilino)-6,7-dimethoxy-quinazoline, (AG1478)], phosphatidylinositol 3-kinase (PI3K) [2-(4-morpholinyl)-8-phenyl-1(4<i>H</i>)-benzopyran-4-one hydrochloride(LY294002) and wortmannin],calcium[1,2-bis(2-aminophenoxy) ethane-<i>N</i>,<i>N</i>,<i>N</i>′,<i>N</i>′-tetraacetic acid-acetoxymethyl ester; BAPTA-AM], phosphatidylinositol-phospholipase C (PLC) [1-[6-[[17β-methoxyestra-1,3,5(10)-trien-17-yl]amino]hexyl]-1<i>H</i>-pyrrole-2,5-dione (U73122)], protein kinase C (PKC) [12-(2-cyanoethyl)-6,7,12, 13-tetrahydro-13-methyl-5-oxo-5<i>H</i>-indolo(2,3-<i>a</i>)pyrrolo(3,4-<i>c</i>)-carbazole (Gö6976), rottlerin, and 3-1-[3-(amidinothio)propyl-1<i>H</i>-indol-3-yl]-3-(1-methyl-1<i>H</i>-indol-3-yl) maleimide (bisindolylmaleimide IX) (Ro 31-8220)], CaM (calmidazolium chloride), CaM kinase II [(8<i>R</i><sup>*</sup>,9<i>S</i><sup>*</sup>,11<i>S</i><sup>*</sup>)-(-)-9-hydroxy-9-methoxycarbonyl-8-methyl-14-<i>n</i>-propoxy-2,3,9, 10-tetrahydro-8,11-epoxy, 1<i>H</i>,8<i>H</i>, 11<i>H</i>-2,7<i>b</i>,11<i>a</i>-triazadibenzo[<i>a,g</i>]cycloocta[<i>cde</i>]trinden-1-one (KT5926) and 1-[<i>N</i>,<i>O</i>-bis(5-isoquinolinesulfonyl)-<i>N</i>-methyl-l-tyrosyl]-4-phenylpiperazine (KN62)], p300 (curcumin), and HDAC (trichostatin A) or transfection with short interfering RNAs for Src, Akt, PKCα, PKCμ, and HDAC4. At gene regulation level, reverse-transcriptase polymerase chain reaction and promoter assays revealed that expression of VCAM-1 was also attenuated by these signaling molecule inhibitors. Moreover, TNF-α induced Akt and CaM kinase II phosphorylation via cascades through Src/EGFR/PI3K and PLC/calcium/CaM, respectively. Finally, activation of Akt and CaM kinase II may eventually lead to the acetylation of histone residues and phosphorylation of histone deacetylase. These findings revealed that TNF-α induced VCAM-1 expression via multiple signaling pathways. Blockade of these pathways may be selectively targeted to reduce neutrophil adhesion via VCAM-1 suppression and attenuation of the inflammatory responses in airway diseases.