Biomaterial Database

Bradykinin-induced asthmatic fibroblast/myofibroblast activities via bradykinin B2 receptor and different MAPK pathways. 2013

Federica Sabatini, and Fabrizio Luppi, and Loredana Petecchia, and Antonino Di Stefano, and Anna M Longo, and Alessandra Eva, and Cristina Vanni, and Pieter S Hiemstra, and Peter J Sterk, and Valentina Sorbello, and Leonardo M Fabbri, and Giovanni A Rossi, and Fabio L M Ricciardolo

Pulmonary Disease Unit, G. Gaslini Institute, Genoa, Italy.

Bradykinin drives normal lung fibroblasts into myofibroblasts, induces fibroblast proliferation and activates mitogen activated protein kinase pathways (MAPK) but its effects on bronchial fibroblasts from asthmatics (HBAFb) have not been yet studied. We studied bradykinin-induced fibroblast proliferation and differentiation and the related intracellular mechanisms in HBAFb compared to normal bronchial fibroblasts (HNBFb). Bradykinin-stimulated HBAFb and HNBFb were used to assess: bradykinin B2 receptor expression by Western blot analysis; cell proliferation by [(3)H] thymidine incorporation; α-smooth muscle actin (SMA) expression/polymerization by Western blot and immunofluorescence; epidermal growth factor (EGF) receptor, extracellular-regulated kinase (ERK) 1/2 and p38 MAPK activation by immunoprecipitation and Western blot, respectively. Constitutive bradykinin B2 receptor and α-SMA expression was higher in HBAFb as compared to HNBFb. Bradykinin increased bradykinin B2 receptor expression in HBAFb. Bradykinin, via bradykinin B2 receptor, significantly increased fibroblast proliferation at lower concentration (10(-11)M) and α-SMA expression/polymerization at higher concentration (10(-6)M) in both cells. Bradykinin increased ERK1/2 and p38 phosphorylation via bradykinin B2 receptor; EGF receptor inhibitor AG1478 and panmetalloproteinase inhibitor GM6001 blocked bradykinin-induced ERK1/2 activation but not p38 phosphorylation. Bradykinin, via bradykinin B2 receptor, induced EGF receptor phosphorylation that was suppressed by AG1478. In HBAFb AG1478, GM6001, the ERK1/2-inhibitor U0126 and the p38 inhibitor SB203580 suppressed bradykinin-induced cell proliferation, but only SB203580 reduced myofibroblast differentiation. These data indicate that bradykinin is actively involved in asthmatic bronchial fibroblast proliferation and differentiation, through MAPK pathways and EGF receptor transactivation, by which bradykinin may contribute to airway remodeling in asthma, opening new horizons for potential therapeutic implications in asthmatic patients.

UI	MeSH Term	Description	Entries
D001920	Bradykinin	A nonapeptide messenger that is enzymatically produced from KALLIDIN in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from MAST CELLS during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter.	Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg,Bradykinin Acetate, (9-D-Arg)-Isomer,Bradykinin Diacetate,Bradykinin Hydrochloride,Bradykinin Triacetate,Bradykinin, (1-D-Arg)-Isomer,Bradykinin, (2-D-Pro)-Isomer,Bradykinin, (2-D-Pro-3-D-Pro-7-D-Pro)-Isomer,Bradykinin, (2-D-Pro-7-D-Pro)-Isomer,Bradykinin, (3-D-Pro)-Isomer,Bradykinin, (3-D-Pro-7-D-Pro)-Isomer,Bradykinin, (5-D-Phe)-Isomer,Bradykinin, (5-D-Phe-8-D-Phe)-Isomer,Bradykinin, (6-D-Ser)-Isomer,Bradykinin, (7-D-Pro)-Isomer,Bradykinin, (8-D-Phe)-Isomer,Bradykinin, (9-D-Arg)-Isomer,Arg Pro Pro Gly Phe Ser Pro Phe Arg
D002454	Cell Differentiation	Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.	Differentiation, Cell,Cell Differentiations,Differentiations, Cell
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D005347	Fibroblasts	Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.	Fibroblast
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000199	Actins	Filamentous proteins that are the main constituent of the thin filaments of muscle fibers. The filaments (known also as filamentous or F-actin) can be dissociated into their globular subunits; each subunit is composed of a single polypeptide 375 amino acids long. This is known as globular or G-actin. In conjunction with MYOSINS, actin is responsible for the contraction and relaxation of muscle.	F-Actin,G-Actin,Actin,Isoactin,N-Actin,alpha-Actin,alpha-Isoactin,beta-Actin,gamma-Actin,F Actin,G Actin,N Actin,alpha Actin,alpha Isoactin,beta Actin,gamma Actin
D001249	Asthma	A form of bronchial disorder with three distinct components: airway hyper-responsiveness (RESPIRATORY HYPERSENSITIVITY), airway INFLAMMATION, and intermittent AIRWAY OBSTRUCTION. It is characterized by spasmodic contraction of airway smooth muscle, WHEEZING, and dyspnea (DYSPNEA, PAROXYSMAL).	Asthma, Bronchial,Bronchial Asthma,Asthmas
D043782	Receptor, Bradykinin B2	A constitutively expressed subtype of bradykinin receptor that may play a role in the acute phase of the inflammatory and pain response. It has high specificity for intact forms of BRADYKININ and KALLIDIN. The receptor is coupled to G-PROTEIN, GQ-G11 ALPHA FAMILY and G-PROTEIN, GI-GO ALPHA FAMILY signaling proteins.	Bradykinin B2 Receptor,Bradykinin Type 2 Receptor,Bradykinin B2 Receptors,Receptor, Bradykinin Type 2,B2 Receptor, Bradykinin,B2 Receptors, Bradykinin,Receptors, Bradykinin B2
D049109	Cell Proliferation	All of the processes involved in increasing CELL NUMBER including CELL DIVISION.	Cell Growth in Number,Cellular Proliferation,Cell Multiplication,Cell Number Growth,Growth, Cell Number,Multiplication, Cell,Number Growth, Cell,Proliferation, Cell,Proliferation, Cellular
D058628	Myofibroblasts	Spindle-shaped cells with characteristic CONTRACTILE PROTEINS and structures that contribute to the WOUND HEALING process. They occur in GRANULATION TISSUE and also in pathological processes such as FIBROSIS.	Myofibroblast