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1.
Eur Respir J ; 39(2): 429-38, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21828027

ABSTRACT

Development of allergic asthma is a complex process involving immune, neuronal and tissue cells. In the lung, Clara cells represent a major part of the "immunomodulatory barrier" of the airway epithelium. To understand the contribution of these cells to the inflammatory outcome of asthma, disease development was assessed using an adjuvant-free ovalbumin model. Mice were sensitised with subcutaneous injections of 10 µg endotoxin-free ovalbumin in conjunction with naphthalene-induced Clara cell depletion. Clara epithelial cell depletion in the lung strongly reduced eosinophil influx, which correlated with decreased eotaxin levels and, moreover, diminished the T-helper cell type 2 inflammatory response, including interleukin (IL)-4, IL-5 and IL-13. In contrast, airway hyperresponsiveness was increased. Further investigation revealed Clara cells as the principal source of eotaxin in the lung. These findings are the first to show that Clara airway epithelial cells substantially contribute to the infiltration of eotaxin-responsive CCR3+ immune cells and augment the allergic immune response in the lung. The present study identifies Clara cells as a potential therapeutic target in inflammatory lung diseases such as allergic asthma.


Subject(s)
Asthma/immunology , Eosinophils/immunology , Hypersensitivity/immunology , Respiratory Mucosa/immunology , Allergens/immunology , Allergens/pharmacology , Animals , Asthma/pathology , Chemokine CCL11/immunology , Chemokine CCL11/metabolism , Cytokines/immunology , Cytokines/metabolism , Eosinophils/pathology , Female , Hypersensitivity/pathology , Mice , Mice, Inbred BALB C , Naphthalenes/immunology , Naphthalenes/pharmacology , Ovalbumin/immunology , Ovalbumin/pharmacology , Receptors, CCR3/metabolism , Respiratory Mucosa/pathology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , T-Lymphocytes/pathology
2.
Eur Respir J ; 36(1): 105-15, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20075049

ABSTRACT

The lung epithelia facilitate wound closure by secretion of various cytokines and growth factors. Nerve growth factor (NGF) has been well described in airway inflammation; however, its likely role in lung repair has not been examined thus far. To investigate the repair function of NGF, experiments were performed in vitro using cultured alveolar epithelial cells and in vivo using a naphthalene-induced model of Clara epithelial cell injury. Both in vitro and in vivo experiments revealed airway epithelial cell proliferation following injury to be dependent on NGF and the expression of its receptor, tropomyosin-receptor-kinase A. Additionally, NGF also augmented in vitro migration of alveolar type II cells. In vivo, transgenic mice over-expressing NGF in Clara cells (NGFtg) did not reveal any proliferation or alteration in Clara cell phenotype. However, following Clara cell specific injury, proliferation was increased in NGFtg and impaired upon inhibition of NGF. Furthermore, NGF also promoted the expression of collagen I and fibronectin in vitro and in vivo during repair, where significantly higher levels were measured in re-epithelialising NGFtg mice. Our study demonstrates that NGF promotes the proliferation of lung epithelium in vitro and the renewal of Clara cells following lung injury in vivo.


Subject(s)
Bronchioles/metabolism , Cell Proliferation , Lung Injury/metabolism , Nerve Growth Factor/metabolism , Animals , Cell Movement , Cells, Cultured , Collagen Type I/analysis , Female , Fibronectins/analysis , Lung Injury/chemically induced , Mice , Mice, Inbred C57BL , Mice, Transgenic , Naphthalenes/toxicity , Protein Kinases/metabolism , Receptors, Nerve Growth Factor/metabolism
3.
Clin Exp Allergy ; 39(8): 1246-54, 2009 Aug.
Article in English | MEDLINE | ID: mdl-19438585

ABSTRACT

INTRODUCTION: The most widely used protocol for the induction of experimental allergic airway inflammation in mice involves sensitization by intraperitoneal (i.p.) injections of the antigen ovalbumin (OVA) used in conjunction with the adjuvant aluminium hydroxide (alum). Although adjuvants are frequently used, there are questions regarding the necessity of alum for murine asthma studies due to the non-physiological nature of this chemical. OBJECTIVE: The objective of this study was to compare experimental asthma phenotypes between adjuvant and adjuvant-free protocols of murine allergic airway inflammation in an attempt to develop a standardized alternative to adjuvant use. METHOD: An adjuvant-free OVA model of experimental asthma was investigated in BALB/c mice using i.p. or subcutaneous (s.c.) sensitization routes. For the s.c. sensitization, beta-galactosidase (beta-gal) was also tested as an antigen. In addition, OVA adjuvant and adjuvant-free sensitization protocols were compared in BALB/c and C57BL/6 mice. Open-field testing was performed to assess the effect of alum on mouse behaviour. RESULTS: Comparison of adjuvant vs. adjuvant-free and i.p. vs. s.c. protocols revealed that both adjuvant use and route of antigen application significantly influenced OVA-specific antibody production. Comparison of adjuvant and adjuvant-free protocols in this study clearly demonstrated the non-requirement of alum for the induction of acute allergic airway inflammation, as both protocols induce a similar disease phenotype. BALB/c mice were significantly more susceptible than C57BL/6 mice to sensitization. Using the improved s.c. adjuvant-free protocol, it was demonstrated that alternative antigens such as beta-gal can also be utilized. Behavioural studies indicated severe distress in mice treated with alum. CONCLUSION: The OVA s.c. adjuvant-free protocol used in this study generates a phenotype comparable to the benchmark adjuvant protocol widely used in the literature. The adjuvant-free alternative avoids the added complication of non-physiological adjuvants that may interfere with asthma treatment or prevention strategies.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Allergens/administration & dosage , Aluminum Hydroxide/administration & dosage , Asthma/physiopathology , Disease Models, Animal , Ovalbumin/administration & dosage , Adjuvants, Immunologic/chemistry , Aluminum Hydroxide/adverse effects , Aluminum Hydroxide/chemistry , Animals , Bronchial Hyperreactivity/physiopathology , Female , Injections, Intraperitoneal , Injections, Subcutaneous , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Phenotype , Sensitivity and Specificity , Skin Tests , beta-Galactosidase/administration & dosage
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