Human airway trypsin-like protease stimulates human bronchial fibroblast proliferation in a protease-activated receptor-2-dependent pathway

Matsushima, Rie; Takahashi, Akira; Nakaya, Yutaka; Maezawa, Hiroshi; Miki, Mari; Nakamura, Yoichi; Ohgushi, Fumitaka; Yasuoka, Susumu

doi:10.1152/ajplung.00098.2005

Cited by 66 publications

(60 citation statements)

References 33 publications

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“…PARs are involved in bronchial fibroblast proliferation, epithelial cell wound healing, and mucus hypersecretion (10,20,21). Our data showing that PAR-1/2 antagonism (Fig.…”

Section: Discussionmentioning

confidence: 55%

Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation

Romberger

Heires

Nordgren

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…PARs are involved in bronchial fibroblast proliferation, epithelial cell wound healing, and mucus hypersecretion (10,20,21). Our data showing that PAR-1/2 antagonism (Fig.…”

Section: Discussionmentioning

confidence: 55%

Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation

Romberger

Heires

Nordgren

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Small 2-mm 3 explants were plated out in 10-cm diameter petri dishes, and outgrowing fibroblasts were trypsinized and passaged in DMEM containing 10% FBS supplemented with antibiotics (50 g/ml streptomycin and 50 U/ml penicillin) as described by Matsushima et al (22). These cells were used between passages 4 and 8 and showed typical fibroblast morphology.…”

Section: Reagentsmentioning

confidence: 99%

Bronchial epithelial cell growth regulation in fibroblast cocultures: the role of hepatocyte growth factor

Skibiński¹,

Elborn²,

Ennis³

2007

American Journal of Physiology-Lung Cellular and Molecular Phys

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Proliferation of bronchial epithelial cells is an important biological process in physiological conditions and various lung diseases. The objective of this study was to determine how bronchial fibroblasts influence bronchial epithelial cell proliferation. The proliferative activity in cocultures was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and direct cells counts. Concentration of cytokines was measured in cell culture supernatants by means of ELISA. In primary cell cocultures, fibroblasts or fibroblast-conditioned medium enhanced 1.85-fold the proliferation of primary bronchial epithelial cells ( P < 0.02) compared with bronchial epithelial cells cultured alone. The proliferative activity in cocultures and in fibroblast-conditioned medium was reduced by neutralizing antibody to hepatocyte growth factor (HGF) and HGF receptor c-met. Neutralizing antibodies to FGF-7 and IGF-1 had no effect. Treatment of fibroblast-epithelial cocultures with anti-IL-6 and anti-TNF-α neutralizing antibodies and with indomethacin decreased production of HGF. These results indicate that cytokines and PGE2may indirectly mediate epithelial cell proliferation via the regulation of HGF in bronchial stromal cells and that HGF plays a crucial role in proinflammatory cytokine-induced proliferation in the experimental system studied.

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“…Both proteases are members of the family of type II transmembrane serine proteases, membraneanchored multidomain proteases, which play complex regulatory roles at the plasma membrane and within the extracellular matrix (7,19). In particular, TMPRSS2 and HAT were shown to regulate cellular functions via protease-activated receptor 2, with TMPRSS2 modulating epithelial sodium channels in human airways (5,26) and HAT stimulating the proliferation of human bronchial fibroblasts (17). HAT was also demonstrated to increase the expression of mucin genes in airway epithelial cells (4).…”

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confidence: 99%

Proteolytic Activation of Influenza Viruses by Serine Proteases TMPRSS2 and HAT from Human Airway Epithelium

Böttcher

Matrosovich

Beyerle

et al. 2006

J Virol

435

447

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Host cell proteases that cleave the hemagglutinin (HA) of influenza viruses in the human respiratory tract are still not identified. Here we cloned two human type II transmembrane serine proteases with known airway localization, TMPRSS2 and HAT, into mammalian expression vector. Cotransfection of mammalian cells with plasmids encoding HA and either protease resulted in HA cleavage in situ. Transient expression of either protease in MDCK cells enabled multicycle replication of influenza viruses in these cells in the absence of exogenous trypsin. These data suggest that TMPRSS2 and HAT are candidates for proteolytic activation of influenza viruses in vivo.The ability of the hemagglutinin protein (HA) of influenza viruses to mediate fusion between viral and endosomal membranes during virus entry into the cell depends on cleavage of fusion-incompetent precursor HA0 into disulfide-linked subunits HA1 and HA2 by a host endoprotease. Cleavage of HA is essential for infection and determines viral pathogenicity and tissue tropism (reviewed in references 8, 10, 11, and 22). Thus, the highly pathogenic avian influenza viruses of subtypes H5 and H7 are cleaved at the multibasic motif R-X-R/K-R by ubiquitous subtilisin-like cellular proteases (11, 23) and cause lethal systemic infection in birds. All other influenza A viruses, including human epidemic and pandemic strains, have a single arginine at the HA cleavage site; these viruses can only be cleaved in a limited number of tissues, such as the intestinal tract in birds and the respiratory tract in birds and mammals (11,22).Early studies demonstrated that influenza viruses with monobasic cleavage site can be proteolytically activated in cell culture by the addition of trypsin (12, 13). Less is known about proteases that cleave influenza viruses under conditions of natural infection. Several trypsin-like proteases isolated from rat and swine lung were shown to support replication of influenza viruses in vitro (3,9,18,25). However, it remains unclear whether these proteases play a role in in vivo infection. In the case of human influenza, specific proteases responsible for HA cleavage in the human respiratory tract have not been identified thus far.In search of such proteases, we use a new approach. Instead of isolating and characterizing influenza virus-activating enzymes from respiratory tissues, we clone and express genes of trypsin-like proteases known to be present in the human airway epithelium and test them for cleavage of HA. We have analyzed here two such proteases, TMPRSS2 (5, 14, 21) and HAT (human airway trypsin-like protease) (4, 24, 27, 28), given their previous detection in the human airways and the availability of their full-length coding sequences. As the source of human genetic material for cloning, we used differentiated cultures of human airway epithelial cells grown at the air-liquid interface in serum-free, hormone-and growth factor-supplemented medium as previously described (6,15). These cultures support multicycle replication of human influenza virus...

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Human airway trypsin-like protease stimulates human bronchial fibroblast proliferation in a protease-activated receptor-2-dependent pathway

Abstract: . Human airway trypsin-like protease stimulates human bronchial fibroblast proliferation in a protease-activated receptor-2-dependent pathway.

Cited by 66 publications

References 33 publications

Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation

Proteases in agricultural dust induce lung inflammation through PAR-1 and PAR-2 activation

Bronchial epithelial cell growth regulation in fibroblast cocultures: the role of hepatocyte growth factor

Proteolytic Activation of Influenza Viruses by Serine Proteases TMPRSS2 and HAT from Human Airway Epithelium

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