Inhibition of NADPH Oxidase 4 (NOX4) Signaling Attenuates Tuberculous Pleural Fibrosis

Abstract

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [NOX] enzymes serve several hemostatic and host defense functions in various lung diseases, but the role of NOX4 signaling in tuberculous pleurisy is not well understood. The role of NOX4 signaling in tuberculous pleural fibrosis was studied using invitro pleural mesothelial cell (PMC) experiments and a murine model of Mycobacterium bovis bacillus Calmette–Guérin (BCG) pleural infection. The production of NOX4 reactive oxygen species (NOX4–ROS) and the epithelial mesenchymal transition (EMT) in PMCs were both induced by heat-killed mycobacterium tuberculosis (HKMT). In cultured PMCs, HKMT-induced collagen-1 synthesis and EMT were blocked by pretreatment with small interfering RNA (siRNA) NOX4. Moreover, NOX4–ROS production and subsequent fibrosis were reduced by treatment with losartan and the toll-like receptor 4 (TLR4) inhibitor TAK-242. The HKMT-induced EMT and intracellular ROS production were mediated by NOX4 via the activation of extracellular signal-regulated kinase (ERK) signaling. Finally, in a BCG-induced pleurisy model, recruitment of inflammatory pleural cells, release of inflammatory cytokines, and thickened mesothelial fibrosis were attenuated by SiNOX4 compared to SiCon. Our study identified that HKMT-induced pleural fibrosis is mediated by NOX4–ERK–ROS via TLR4 and Angiotensin II receptor type1 (AT1R). There results suggest that NOX4 may be a novel therapeutic target for intervention in tuberculous pleural fibrosis.

<p>The Protective Role of Tanshinone IIA in Silicosis Rat Model via TGF-β1/Smad Signaling Suppression, NOX4 Inhibition and Nrf2/ARE Signaling Activation</p>

“…NOX4 is upregulated in fibrosis, and its genetic or pharmacological inhibition decreases ECM deposition and TGF-β1-dependent fibrosis-promoting response significantly. 38,39 Our result suggested that Tan IIA reduced the upregulated mRNA and protein levels of NOX4 in silicosis rats. Thus, the antifibrotic effect of Tan IIA may also be attributed to NOX4 inhibition induced decrease in oxidative stress.…”

Oscillatory Shear Stress Induces Oxidative Stress via TLR4 Activation in Endothelial Cells

“…Several studies have reported the interrelation between TLR4 and NOXs. Wang et al elaborated that TLR4 blocking reduced salt-induced prehypertension response via NADPH oxidases [28], while a study from Kim et al also suggested a regulation effect of NOX4 on TLR4 [29]. We wondered the directional regulation; hence, siRNA against TLR4 or NOX2 were used prior to OSS exposure in ECs.…”

Plasma concentrations of NOX4 are predictive of successful liberation from mechanical ventilation and 28-day mortality in critically ill patients

“…Among the Nox family, NOX4is upregulated in several pulmonary diseases including tuberculous brosis, idiopathic pulmonary brosis, and lung cancer [26,27]. Ling et al, reported signi cantly higher NOX4 levels in a rat model of ventilator-induced lung injury [28].…”

“…A total of 184 patients were enrolled; of these, only97patients were successfully extubatedwithin3 weeks. Patients with extubation failure were signi cantly older (76 vs.69years, P = 0.003).The APACHE II score and SOFA score in the failed extubation group were signi cantly higher than that in the successful extubation group [median (IQR), APACHE:23 (20)(21)(22)(23)(24)(25)(26)(27)(28) vs. 19 (15)(16)(17)(18)(19)(20)(21)(22)(23); P<0.001, SOFA: 9 (7-12) vs 6 (5-9); P<0.001];however, no signi cant between-group difference was observed with respect to Charlson comorbidity index [2(1, 3) vs. 2 (1, 3), P = 0.225].The indications for intubation and the proportion of patients with pneumonia at admission were not different between the two groups.…”