Isatin down-regulates expression of atrial natriuretic peptide receptor A and inhibits airway inflammation in a mouse model of allergic asthma.
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.
Kandasamy
R
R
Division of Allergy and Immunology-Joy McCann Culverhouse Airway Disease Center, Dept. of Internal Medicine and Nanomedicine Research Center, College of Medicine, Tampa, FL, USA.
Park
S J
SJ
Boyapalle
S
S
Mohapatra
S
S
Hellermann
G R
GR
Lockey
R F
RF
Mohapatra
S S
SS
D000281:Administration, Intranasal; D000818:Animals; D001249:Asthma / Q000188:drug therapy*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D048271:Chitosan / Q000008:administration & dosage; D006152:Cyclic GMP / Q000737:chemistry; D016207:Cytokines / Q000737:chemistry; D005260:Female; D007249:Inflammation / Q000188:drug therapy; D007510:Isatin / Q000008:administration & dosage*; D007962:Leukocytes / Q000737:chemistry; D008168:Lung / Q000737:chemistry / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D053769:Nanocapsules / Q000008:administration & dosage; D010047:Ovalbumin / Q000276:immunology; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors*
D016207:Cytokines; D053769:Nanocapsules; D007510:Isatin; D010047:Ovalbumin; D048271:Chitosan; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP