Inhibition of chronic airway inflammation and remodeling by galectin-3 gene therapy in a murine model.
We previously demonstrated that treatment of acute asthmatic rats with gene therapy using plasmid-encoding Galectin-3 (Gal-3) resulted in an improvement of cellular and functional respiratory parameters. The next question that we wanted to clarify was if in a chronic situation where the treated animal continues to inhale the Ag, does this procedure prevent the chronicity and the remodeling? Chronic inflammation was induced by intranasal administration of OVA over a period of 12 wk. In the treated group, the Gal-3 gene was introduced by intranasal instillation in 50 mul of plasmid-encoding Gal-3. Noninvasive airway responsiveness to methacholine was tested at different times. Cells were obtained by bronchoalveolar lavage and used for RNA extraction and cytometric studies. Eosinophils were counted in blood and bronchoalveolar lavage fluid. Real-time PCR was used to measure Gal-3 and cytokine mRNA expression in lung. Lungs were paraffined and histologic analyses were performed (H&E, periodic acid-Schiff, and Masson Trichrome stain). Our results showed that 12 wk after the first intranasal Ag instillation in chronically asthmatic mice, treatment with the Gal-3 gene led to an improvement in the eosinophil count and the normalization of hyperresponsiveness to methacholine. Concomitantly, this treatment resulted in an improvement in mucus secretion and subepithelial fibrosis in the chronically asthmatic mice, with a quantitatively measured reduction in lung collagen, a prominent feature of airway remodeling. Plasmid-encoding Gal-3 acts as a novel treatment for chronic asthma in mice producing nearly complete blockade of Ag responses with respect to eosinophil airway accumulation, airway hyperresponsiveness, and remodeling.
López
Esther
E
Immunology Department, Fundación Jiménez Díaz Capio, Madrid, Spain.
del Pozo
Victoria
V
Miguel
Teresa
T
Sastre
Beatriz
B
Seoane
Carmen
C
Civantos
Esther
E
Llanes
Elena
E
Baeza
M Luisa
ML
Palomino
Pilar
P
Cárdaba
Blanca
B
Gallardo
Soledad
S
Manzarbeitia
Félix
F
Zubeldia
José M
JM
Lahoz
Carlos
C
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001249:Asthma / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D016535:Bronchial Hyperreactivity / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D001992:Bronchoalveolar Lavage Fluid; D002908:Chronic Disease; D003094:Collagen / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D037502:Galectin 3 / Q000235:genetics* / Q000627:therapeutic use*; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007958:Leukocyte Count; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D010047:Ovalbumin / Q000276:immunology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D037502:Galectin 3; D007074:Immunoglobulin G; D007073:Immunoglobulin E; D010047:Ovalbumin; D003094:Collagen