Cigarette Smoke Induces MUC5AC Protein Expression through the Activation of Sp1

Di, Y. Peter; Zhao, Jiang; Harper, Richart W

doi:10.1074/jbc.m111.334375

Cited by 79 publications

(62 citation statements)

References 38 publications

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“…Although WCS has been frequently used to model smoking-related lung disease (24,29) and the reduced CFTR function observed here is consistent with prior studies (2,9,24,29), the experiments conducted rely on acute CSE and are unlikely to capture the complexity of the airway environment in patients with COPD, such as airway inflammation, disrupted proteolytic balance, and ER stress (3,31,47,48). Although the conclusion that CFTR activation by roflumilast contributes to therapeutic benefit in patients with chronic bronchitis is supported by specificity controls, as an efficacious activator of intracellular cAMP, roflumilast may also improve the function of surface epithelia via other pathways.…”

Section: Original Researchsupporting

confidence: 79%

“…The degree of CFTR inhibition by WCS was sufficient to reduce ASL depth, which is known to decrease the efficiency of MCT (30). Because the severity of the ion transport and ASL abnormalities was intermediate compared with the defect observed in CF epithelial cells, it seems likely that this decrement is sufficient to initiate a cascade of mucus retention and infection in vivo, particularly if present over multiple years and combined with enhanced mucus expression also caused by cigarette smoking (2,31).…”

Section: Discussionmentioning

confidence: 99%

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Cystic Fibrosis Transmembrane Conductance Regulator Activation by Roflumilast Contributes to Therapeutic Benefit in Chronic Bronchitis

Lambert

Raju²,

Tang

et al. 2014

Am J Respir Cell Mol Biol

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Cigarette smoking causes acquired cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction and is associated with delayed mucociliary clearance and chronic bronchitis. Roflumilast is a clinically approved phosphodiesterase 4 inhibitor that improves lung function in patients with chronic bronchitis. We hypothesized that its therapeutic benefit was related in part to activation of CFTR. Primary human bronchial epithelial (HBE) cells, Calu-3, and T84 monolayers were exposed to whole cigarette smoke (WCS) or air with or without roflumilast treatment. CFTRdependent ion transport was measured in modified Ussing chambers. Airway surface liquid (ASL) was determined by confocal microscopy. Intestinal fluid secretion of ligated murine intestine was monitored ex vivo. Roflumilast activated CFTR-dependent anion transport in normal HBE cells with a half maximal effective concentration of 2.9 nM. Roflumilast partially restored CFTR activity in WCS-exposed HBE cells (5.3 6 1.1 mA/cm 2 vs. 1.2 6 0.2 mA/cm 2 [control]; P , 0.05) and was additive with ivacaftor, a specific CFTR potentiator approved for the treatment of CF. Roflumilast improved the depleted ASL depth of HBE monolayers exposed to WCS (9.0 6 3.1 mm vs. 5.6 6 2.0 mm [control]; P , 0.05), achieving 79% of that observed in air controls. CFTR activation by roflumilast also induced CFTR-dependent fluid secretion in murine intestine, increasing the wet:dry ratio and the diameter of ligated murine segments. Roflumilast activates CFTR-mediated anion transport in airway and intestinal epithelia via a cyclic adenosine monophosphate-dependent pathway and partially reverses the deleterious effects of WCS, resulting in augmented ASL depth. Roflumilast may benefit patients with chronic obstructive pulmonary disease with chronic bronchitis by activating CFTR, which may also underlie noninfectious diarrhea caused by roflumilast.

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Section: Original Researchsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Cystic Fibrosis Transmembrane Conductance Regulator Activation by Roflumilast Contributes to Therapeutic Benefit in Chronic Bronchitis

Lambert

Raju²,

Tang

et al. 2014

Am J Respir Cell Mol Biol

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“…A recent study demonstrated that MUC5B, but not MUC5AC, is essential for mucociliary clearance activity and the prevention of bacterial spread from the nasal cavity to the lower respiratory tract (312). Mucus secretion and mucociliary clearance are enhanced in the presence of inflammatory mediators (313) and microbial pathogens (314)(315)(316) and following exposure to cigarette smoke (317). Antimicrobial substances, including enzymes (lysozyme), protease inhibitors (secretory leukoprotease inhibitor, elastase inhibitor, ␣1-antiprotease, and antichymotrypsin), antimicrobial peptides (␤-defensins and L37), and oxidants (nitric oxide and hydrogen peroxide), are secreted by epithelial cells into the airway surface liquid and provide a further line of defense against microbes (318).…”

Section: Protecting the Cns From Microbial Invasion Via The Nasal Cavitymentioning

confidence: 99%

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

et al. 2014

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SUMMARY The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). In addition, cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Nonetheless, a range of pathogenic microbes make their way to the CNS, and the resulting infections can cause significant morbidity and mortality. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. In this review, we compare the mechanisms by which bacterial pathogens reach the CNS and infect the brain. In particular, we focus on recent data regarding mechanisms of bacterial translocation from the nasal mucosa to the brain, which represents a little explored pathway of bacterial invasion but has been proposed as being particularly important in explaining how infection with Burkholderia pseudomallei can result in melioidosis encephalomyelitis.

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“…Di 48 ) and 0.05 mg pCMV-b-galactosidase (b-gal) (Clontech) using Effectene (Qiagen). The TGF-b1 promoter-luciferase plasmid was also used as a template to construct new plasmids with deletion of the SREBP-1 or the Sp1 binding site using overlapping primer pairs.…”

Section: Luciferase Assaymentioning

confidence: 99%

SREBP-1 Mediates Angiotensin II-Induced TGF-β1 Upregulation and Glomerular Fibrosis

Wang

Chen

et al. 2015

Journal of the American Society of Nephrology

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Angiotensin II is an important mediator of CKD of diverse etiology. A common pathologic feature of CKD is glomerular fibrosis, a central mediator of which is the profibrotic cytokine TGF-b. The mechanisms underlying the induction of TGF-b and matrix by angiotensin II are not completely understood. Recent studies showed that overexpression of the transcription factor SREBP-1 induces glomerular sclerosis and that angiotensin II can activate SREBP-1 in tubular cells. We thus studied whether SREBP-1 is activated by angiotensin II and mediates angiotensin II-induced profibrogenic responses in primary rat mesangial cells. Treatment of cells with angiotensin II induced the upregulation and activation of SREBP-1. Angiotensin II-induced activation of SREBP-1 required signaling through the angiotensin II type I receptor and activation of PI3K/Akt in addition to the chaperone SCAP and protease S1P. Notably, angiotensin II-induced endoplasmic reticulum stress was identified as a key mediator of Akt-SREBP-1 activation, and inhibition of endoplasmic reticulum stress or SREBP-1 prevented angiotensin II-induced SREBP-1 binding to the TGF-b promoter, TGF-b upregulation, and downstream fibronectin upregulation. Endoplasmic reticulum stress alone, however, did not induce TGF-b upregulation despite activating SREBP-1. Although not required for SREBP-1 activation by angiotensin II, EGF receptor signaling was necessary for activation of the SREBP-1 cotranscription factor Sp1, which provided a required second signal for TGF-b upregulation. In vivo, endoplasmic reticulum stress and SREBP-1-dependent effects were induced in glomeruli of angiotensin II-infused mice, and administration of the SREBP inhibitor fatostatin prevented angiotensin II-induced TGF-b upregulation and matrix accumulation. SREBP-1 and endoplasmic reticulum stress thus provide potential novel therapeutic targets for the treatment of CKD.

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Cigarette Smoke Induces MUC5AC Protein Expression through the Activation of Sp1

Cited by 79 publications

References 38 publications

Cystic Fibrosis Transmembrane Conductance Regulator Activation by Roflumilast Contributes to Therapeutic Benefit in Chronic Bronchitis

Cystic Fibrosis Transmembrane Conductance Regulator Activation by Roflumilast Contributes to Therapeutic Benefit in Chronic Bronchitis

Pathogens Penetrating the Central Nervous System: Infection Pathways and the Cellular and Molecular Mechanisms of Invasion

SREBP-1 Mediates Angiotensin II-Induced TGF-β1 Upregulation and Glomerular Fibrosis

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