Chest
Neutrophil Elastase Induces MUC5AC Messenger RNA Expression by an Oxidant-Dependent Mechanism
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Cell Culture
Two respiratory epithelial model systems were utilized for these studies: A549 cells (American Type Culture Collection; Manassas, VA), a lung adenocarcinoma cell line that expresses both MUC5AC messenger RNA and glycoprotein; and normal human bronchial epithelial cells (NHBE; Clonetics; San Diego, CA) maintained in an air-liquid interface culture system. Both cell types were grown and maintained as previously described.3
Cell Stimulation
All studies were performed when A549 cells are 90 to 95% confluent. Cells
NE-Induced MUC5AC Messenger RNA Expression Is Inhibited by Oxidant Scavengers
NE increases MUC5AC messenger RNA expression by enhancing messenger RNA stability, but the signaling pathway of this mechanism is not known. We hypothesized that ROS mediate the NE-regulated increase in MUC5AC messenger RNA stability. To test this hypothesis, we treated cells with DMTU, a scavenger of hydroxyl radical, associated hydroxylated products, and peroxynitrite4 prior to and during NE stimulation. DMTU had no effect on baseline MUC5AC messenger RNA. Importantly, DMTU (40 mM) inhibited
Discussion
In this study, we demonstrated that NE enhancement of MUC5AC messenger RNA levels was dependent on the production of intracellular oxidants or an alteration in the redox state of the cell. DMTU inhibited NE-induced MUC5AC expression, suggesting a role for hydroxyl radical, hydroxylated products, or peroxynitrite in MUC5AC gene regulation. Recently, we have reported that NE increases MUC5AC messenger RNA levels by a posttranscriptional mechanism.3 Collectively, this suggests that ROS may play a
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Mucin genes and gene products
Cited by (63)
The role of autophagy in the overexpression of MUC5AC in patients with chronic rhinosinusitis
2019, International ImmunopharmacologyCitation Excerpt :For example, Scutellarin attenuates human-neutrophil-elastase-induced mucus production by inhibiting the PKC-ERK signaling pathway [45]. In human bronchial epithelial cells and human lung cancer cells, HNE induces MUC5AC expression [46,47]. Another study showed that HNE induces MUC5AC overexpression in patients with CRS via tumor necrosis factor-α converting enzyme, which subsequently produces excessive MUC in patients with CRSsNP or CRSwNP [7].
Bombesin receptor-activated protein regulates neutrophil elastase-induced mucin5AC hypersecretion in human bronchial epithelial cells
2017, Experimental Cell ResearchCitation Excerpt :MUC5AC synthesis and gene expression are up-regulated by a variety of stimulators such as cytokines, lipopolysaccharide and cigarette smoke [11–14]. It has been demonstrated that the expression of MUC5AC is regulated by multiple signaling pathways, including the epidermal growth factor receptor (EGFR), mitogen-activated protein kinase (MAPK), and signal transducers and activators of transcription pathways [15–17]. Neutrophil elastase (NE), a serine protease secreted by neutrophils that exists in high concentrations in the airway secretions of these patients, is one of the most potent inducers for mucous overproduction [18–20].
Increased expression of MUC5AC and MUC5B promoting bacterial biofilm formation in chronic rhinosinusitis patients
2015, Auris Nasus LarynxCitation Excerpt :All these researches demonstrated the adhesion of bacteria to the human nasal mucins. On the contrary, the formation of BBF aggravates inflammatory, and inflammatory mediators, such as IL-6, TNF-α, neutrophil elastase, and bacterial endotoxins in turn upregulate mucins expression [20,21], which come into a vicious circle. Of course, fungus as well formed biofilm.
Oxidative stress and antioxidant therapy in cystic fibrosis
2012, Biochimica et Biophysica Acta - Molecular Basis of DiseaseCitation Excerpt :In this respect, a direct link has been proposed between the excessive production of intracellular H2O2 and the elevated expression of IL-6 and IL-8, the most abundant pro-inflammatory cytokine and neutrophilic chemokine found in CF airways [54], which has been further confirmed [59]. Moreover, oxidants could be synergic in the induction of mucins, as promoted by neutrophil elastase, which further impairs ASL fluidity in CF [60]. Finally, bacterial infection with P. aeruginosa strains releasing the toxin pyocyanin (PCN) has been shown to reduce ion transport through the CFTR channel, thus potentially counteracting the therapeutic effects of correctors and potentiators of mutated CFTR protein [61,62].
Pathogenesis and Disease Mechanisms of Occupational Asthma
2011, Immunology and Allergy Clinics of North AmericaCitation Excerpt :It remains unclear if increased levels of oxidative stress observed in asthmatic individuals is a cause of disease or rather a result of ongoing inflammation in the airways, which itself produces reactive oxygen species. Regardless of the source, oxidative stress is thought to aggravate asthmatic airway inflammation via multiple mechanisms, including proinflammatory mediators, and effects on smooth muscle and mucous secretion.117–119 The molecular mechanisms by which oxidative stress affects cellular responses are beginning to be deciphered.
Supported by the Cystic Fibrosis Foundation, The North Carolina Biotechnology Center, and Duke University Medical Center.