Inhibition of neutrophil elastase attenuates airway hyperresponsiveness and inflammation in a mouse model of secondary allergen challenge: neutrophil elastase inhibition attenuates allergic airway responses.
BACKGROUND
Chronic asthma is often associated with neutrophilic infiltration in the airways. Neutrophils contain elastase, a potent secretagogue in the airways, nonetheless the role for neutrophil elastase as well as neutrophilic inflammation in allergen-induced airway responses is not well defined. In this study, we have investigated the impact of neutrophil elastase inhibition on the development of allergic airway inflammation and airway hyperresponsiveness (AHR) in previously sensitized and challenged mice.


METHODS
BALB/c mice were sensitized and challenged (primary) with ovalbumin (OVA). Six weeks later, a single OVA aerosol (secondary challenge) was delivered and airway inflammation and airway responses were monitored 6 and 48 hrs later. An inhibitor of neutrophil elastase was administered prior to secondary challenge.


RESULTS
Mice developed a two-phase airway inflammatory response after secondary allergen challenge, one neutrophilic at 6 hr and the other eosinophilic, at 48 hr. PAR-2 expression in the lung tissues was enhanced following secondary challenge, and that PAR-2 intracellular expression on peribronchial lymph node (PBLN) T cells was also increased following allergen challenge of sensitized mice. Inhibition of neutrophil elastase significantly attenuated AHR, goblet cell metaplasia, and inflammatory cell accumulation in the airways following secondary OVA challenge. Levels of IL-4, IL-5 and IL-13, and eotaxin in BAL fluid 6 hr after secondary allergen challenge were significantly suppressed by the treatment. At 48 hr, treatment with the neutrophil elastase inhibitor significantly reduced the levels of IL-13 and TGF-β1 in the BAL fluid. In parallel, in vitro IL-13 production was significantly inhibited in spleen cells from sensitized mice.


CONCLUSIONS
These data indicate that neutrophil elastase plays an important role in the development of allergic airway inflammation and hyperresponsiveness, and would suggest that the neutrophil elastase inhibitor reduced AHR to inhaled methacholine indicating the potential for its use as a modulator of the immune/inflammatory response in both the neutrophil- and eosinophil-dominant phases of the response to secondary allergen challenge.
Department of Hematology, Oncology, Allergy and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Hikari
H
Koga
Nobuaki
N
Miyahara
Yasuko
Y
Fuchimoto
Genyo
G
Ikeda
Koichi
K
Waseda
Katsuichiro
K
Ono
Yasushi
Y
Tanimoto
Mikio
M
Kataoka
Erwin W
EW
Gelfand
Mitsune
M
Tanimoto
Arihiko
A
Kanehiro
D000485:Allergens; D000818:Animals; D001980:Bronchi / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy* / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D020556:Neutrophil Infiltration / Q000502:physiology; D010047:Ovalbumin / Q000276:immunology; D053491:Proteinase Inhibitory Proteins, Secretory / Q000494:pharmacology*; D044464:Receptor, PAR-2 / Q000096:biosynthesis / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000188:drug therapy* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*
D000485:Allergens; D018925:Chemokines; D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D044464:Receptor, PAR-2; D013449:Sulfonamides; D010047:Ovalbumin; C069195:sivelestat; D019272:Leukocyte Elastase; D005998:Glycine