Isatin down-regulates expression of atrial natriuretic peptide receptor A and inhibits airway inflammation in a mouse model of allergic asthma

• Published in: International immunopharmacology Vol. 10; no. 2; pp. 218 - 225
• Main Authors: Kandasamy, R., Park, S.J., Boyapalle, S., Mohapatra, S., Hellermann, G.R., Lockey, R.F., Mohapatra, S.S.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01-02-2010; Elsevier
• Subjects: Administration, Intranasal; Animals; Asthma; Asthma - drug therapy; Atrial; Biological and medical sciences; Bronchoalveolar Lavage Fluid - chemistry; Chitosan - administration & dosage; Chronic obstructive pulmonary disease, asthma; Cyclic GMP - chemistry; Cytokines - chemistry; Female; Inflammation - drug therapy; Isatin; Isatin - administration & dosage; Leukocytes - chemistry; Lung - chemistry; Lung - pathology; Medical sciences; Mice; Mice, Inbred BALB C; Nanocapsules - administration & dosage; Nanoparticles; Natriuretic; NPRA; Ovalbumin - immunology; Pharmacology. Drug treatments; Pneumology; Receptors, Atrial Natriuretic Factor - antagonists & inhibitors; Nanoparticles; Natriuretic; NPRA; Atrial; Isatin; Asthma; Allergy; Animal model; Nanoparticle; Toxicity; Esterases; Respiratory system; Respiratory tract; Microparticle; Bronchus disease; Anticholinesterase agent; Obstructive pulmonary disease; Immunopathology; Lung disease; Atrium; ANPA receptor; Enzyme; Respiratory disease; Rodentia; Enzyme inhibitor; Inflammation; Cholinesterase; Carboxylic ester hydrolases; Vertebrata; Mammalia; Mouse; Hydrolases; Indole derivatives
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2009.11.003

Isatin, an endogenous indole compound, prevents atrial natriuretic peptide (ANP) from signaling through its cell-surface receptor, NPRA. Allergic airway inflammation has been linked to natriuretic peptide signaling and blocking this signaling axis in the lung prevents allergen-induced pathology. In this study we encapsulated isatin in chitosan nanoparticles and tested them in a mouse model of allergic asthma by intranasal delivery to the lung. Isatin nanocapsules reduced lung pathology by blocking ANP signaling, but surprisingly also by reducing the expression of NPRA. Ovalbumin-allergic mice were treated intranasally with isatin-containing chitosan nanocapsules either before or after allergen challenge, and lung function, cytokine levels, histopathology and cellular infiltration were determined. ANP activity was quantitated by measuring changes in intracellular cyclic GMP and changes in NPRA levels were determined. For comparison with isatin's effects, the expression of the receptor was inhibited with small interfering RNA against NPRA mRNA. Isatin nanocapsules administered locally to the lung reduced cGMP production and NPRA expression and protected allergic mice from airway hyperreactivity and lung inflammation when given either before or after allergen challenge. Leukocyte infiltration was reduced and lung cytokine profiles showed a repolarization from a Th2-like to a Th1-like phenotype. Isatin nanocapsules administered locally to the lung inhibit NPRA signaling but also are capable of lowering the expression of NPRA, thus effectively reducing inflammation in a mouse model of allergic asthma. Pharmacological intervention to reduce NPRA activity through the inflammatory natriuretic peptide axis in the lung may be a useful adjunct therapy for treating lung disease.