Activation of protease-activated receptor-2 reduces airways inflammation in experimental allergic asthma.
BACKGROUND
Proteinase-activated receptors (PAR)-2 are members of the family of G-protein-coupled receptors activated by proteases. These receptors are widely expressed in several tissues and in virtually all cells involved in rhinitis and asthma. In particular, proteinases activating PAR-2 may affect airway functions and play a role in human diseases.


OBJECTIVE
Assessment of the role of PAR-2 in bronchoconstriction, airway responsiveness and immune response after allergic challenge, in rabbits sensitized to Par j 1, the major allergen of Parietaria judaica pollen.


METHODS
Evaluation of antigen challenge in rabbits treated with PAR-2-activating peptide (PAR-2AP) (SLIGRL) or the scrambled peptide LSIGRL or vehicle immediately before allergen exposure measuring airway responsiveness. Characterization of bronchoalveolar lavage (BAL) following histamine challenge and phenotype analysis of cells by flow cytometry and analysis of cytokine production by quantitative PCR.


RESULTS
PAR-2AP pre-treatment, but not the scrambled peptide, was able to significantly inhibit bronchoconstriction, airway hyper-responsiveness and to modulate the immune response induced by allergic challenge in sensitized rabbits. The phenotype analysis of the cells recovered from BAL showed an increase in RLA-DR-positive cells while RTLA-positive cells were unchanged. IFN-gamma and IL-2 production were inhibited, with a concomitant increase in IL-10 of about 10-fold over the control values.


CONCLUSIONS
In this experimental model, PAR-2 modulates bronchoconstriction interfering with antigen challenge-induced immune response in rabbits sensitized and challenged to Par j 1.
D'Agostino
B
B
Department of Experimental Medicine, Section of Pharmacology, Faculty of Medicine and Surgery, Second University of Naples, Naples, Italy. bruno.dagostino@unina2.it
Roviezzo
F
F
De Palma
R
R
Terracciano
S
S
De Nardo
M
M
Gallelli
L
L
Abbate
G F
GF
D'Aiuto
E
E
Russo
M
M
Cirino
G
G
Rossi
F
F
D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D016084:Bronchoconstriction / Q000276:immunology*; D005260:Female; D006632:Histamine / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000276:immunology*; D008297:Male; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010940:Plant Proteins / Q000276:immunology; D011817:Rabbits; D044464:Receptor, PAR-2 / Q000819:agonists* / Q000502:physiology; D012130:Respiratory Hypersensitivity / Q000276:immunology* / Q000473:pathology
D000485:Allergens; D007376:Interleukin-2; D009842:Oligopeptides; C083860:Par j I protein, Parietaria judaica; D010455:Peptides; D010940:Plant Proteins; D044464:Receptor, PAR-2; C099570:seryl-leucyl-isoleucyl-glycyl-arginyl-leucine; D006632:Histamine; D007371:Interferon-gamma