Human Neutrophil Elastase Induces Hypersecretion of Mucin from Well-Differentiated Human Bronchial Epithelial Cells in Vitro via a Protein Kinase Cδ-Mediated Mechanism

Park, Jin‐Ah; He, Fang; Martin, Linda D.; Li, Yuehua; Chorley, Brian N.; Adler, Kenneth B.

doi:10.1016/s0002-9440(10)62040-8

Cited by 102 publications

(95 citation statements)

References 58 publications

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“…hypersecretion in human bronchial epithelial cells (37,38) and caused mucus metaplasia in mouse lungs (43). It is plausible that mucus metaplasia occurs in CA-IKKb-expressing mice beyond the timeframe of investigation within the current study, which may contribute to potentially chronic abnormalities in respiratory mechanics, although these possibilities remain to be formally tested.…”

Section: Discussionmentioning

confidence: 88%

“…Therefore, the marked presence of neutrophils might contribute to increases in AHR in CA-IKKb-expressing mice. Neutrophils are capable of generating a number of mediators, such as reactive oxygen and nitrogen species, matrix metalloproteinases, and elastase, which have been linked to increases in AHR directly, or indirectly after stimulation of ASM cells or airway epithelial cells (35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

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Nuclear Factor-κB Activation in Airway Epithelium Induces Inflammation and Hyperresponsiveness

Pantano¹,

Ather²,

Alcorn³

et al. 2008

Am J Respir Crit Care Med

113

123

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Rationale: Nuclear factor (NF)-kB is a prominent proinflammatory transcription factor that plays a critical role in allergic airway disease. Previous studies demonstrated that inhibition of NF-kB in airway epithelium causes attenuation of allergic inflammation. Objectives: We sought to determine if selective activation of NF-kB within the airway epithelium in the absence of other agonists is sufficient to cause allergic airway disease. Methods: A transgenic mouse expressing a doxycycline (Dox)-inducible, constitutively active (CA) version of inhibitor of kB (IkB) kinase-b (IKKb) under transcriptional control of the rat CC10 promoter, was generated. Measurements and Main Results: After administration of Dox, expression of the CA-IKKb transgene induced the nuclear translocation of RelA in airway epithelium. IKKb-triggered activation of NF-kB led to an increased content of neutrophils and lymphocytes, and concomitant production of proinflammatory mediators, responses that were not observed in transgenic mice not receiving Dox, or in transgenenegative littermate control animals fed Dox. Unexpectedly, expression of the IKKb transgene in airway epithelium was sufficient to cause airway hyperresponsiveness and smooth muscle thickening in absence of an antigen sensitization and challenge regimen, the presence of eosinophils, or the induction of mucus metaplasia.Conclusions: These findings demonstrate that selective activation NFkB in airway epithelium is sufficient to induce airway hyperresponsiveness and smooth muscle thickening, which are both critical features of allergic airway disease.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Nuclear Factor-κB Activation in Airway Epithelium Induces Inflammation and Hyperresponsiveness

Pantano¹,

Ather²,

Alcorn³

et al. 2008

Am J Respir Crit Care Med

113

123

View full text Add to dashboard Cite

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“…None of the treatments generated a toxic response in the cells, as assessed by LDH retention/release (data not shown) (28).…”

Section: Cytotoxicitymentioning

confidence: 93%

A Peptide Against the N-Terminus of Myristoylated Alanine-Rich C Kinase Substrate Inhibits Degranulation of Human LeukocytesIn Vitro

Takashi

Park²,

Fang³

et al. 2006

Am J Respir Cell Mol Biol

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Leukocytes synthesize a variety of inflammatory mediators that are packaged and stored in the cytoplasm within membrane-bound granules. Upon stimulation, the cells secrete the granule contents via an exocytotic process whereby the granules translocate to the cell periphery, the granule membranes fuse with the plasma membrane, and the granule contents are released extracellularly. We have reported previously that another exocytotic process, release of mucin by secretory cells of the airway epithelium, is regulated by the myristoylated alanine-rich C kinase substrate ( Keywords: MARCKS protein; leukocytes; degranulationLeukocytes synthesize a number of inflammatory mediators that are packaged and stored in cytoplasmic membrane-bound granules. These mediators include myeloperoxidase (MPO) in neutrophils (1), eosinophil peroxidase (EPO) and major basic pro- (2), lysozyme in monocytes/macrophages (3, 4), and granzyme in natural killer (NK) cells and cytotoxic lymphocytes (5-8). These mediators are released at sites of injury and contribute to inflammation and repair in the lung and elsewhere. Leukocytes release these granules via an exocytotic mechanism (9, 10), but the regulatory molecules and specific pathways involved in the exocytotic process have not been fully described.Several exogenous stimuli can provoke degranulation of leukocytes via a pathway that involves activation of protein kinase C (PKC) and subsequent phosphorylation events (9-13). MARCKS (myristoylated alanine-rich C kinase substrate), a ubiquitous phosphorylation target of PKC, is highly expressed in leukocytes (14-16). We have previously demonstrated that MARCKS protein is involved in exocytotic secretion of mucin by goblet cells that line the respiratory airways (17, 18). In airway epithelial cells, the N-terminus of MARCKS seems to be integral to the secretory process. The mechanism seems to involve the binding of MARCKS to membranes of intracellular mucin granules because a peptide against the N-terminus of MARCKS blocked mucin secretion and binding of MARCKS to mucin granule membranes in these cells (18). Because MARCKS is a prominent protein in leukocytes, we investigated whether or not MARCKS, and specifically its N-terminus, could play a role in leukocyte degranulation.In these studies, we used four different leukocyte types or models that secrete specific granule contents in response to phorbol ester-induced activation of PKC. First, neutrophils were isolated from human blood, and the in vitro release of MPO by these cells was assessed. Due to difficulties in isolating sufficient amounts of other leukocyte types from blood, we investigated the release of membrane-bound inflammatory mediators from commercially available human leukocyte cell lines. The human promyelocytic cell line HL-60 clone 15 was used to assess secretion of , the monocytic leukemia cell line U937 was used to assess secretion of lysozyme (3,4,23), and the lymphocyte NK cell line NK-92 was used to assess the release of granzyme (6-8). In all cases, the cells were preinc...

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“…Other factors can also induce mucus. For example, LPS can stimulate low-level mucous production in IL-13-deficient mice (17), and many studies have shown a role for human neutrophil elastase in mucous production (19,20). Even in light of the seminal studies of mucin gene expression by Carol Basbaum (21,22), there is only a rudimentary understanding of how these mediators stimulate mucins, the contribution of different mucins to the protective response, and which pathways are active in human disease.…”

Section: Il-13 Stimulates Mucus In Asthmamentioning

confidence: 99%

Mucus in chronic airway diseases: sorting out the sticky details

Cohn¹

2006

Journal of Clinical Investigation

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Human Neutrophil Elastase Induces Hypersecretion of Mucin from Well-Differentiated Human Bronchial Epithelial Cells in Vitro via a Protein Kinase Cδ-Mediated Mechanism

Cited by 102 publications

References 58 publications

Nuclear Factor-κB Activation in Airway Epithelium Induces Inflammation and Hyperresponsiveness

Nuclear Factor-κB Activation in Airway Epithelium Induces Inflammation and Hyperresponsiveness

A Peptide Against the N-Terminus of Myristoylated Alanine-Rich C Kinase Substrate Inhibits Degranulation of Human LeukocytesIn Vitro

Mucus in chronic airway diseases: sorting out the sticky details

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