Corticotropin-releasing hormone deficiency increases allergen-induced airway inflammation in a mouse model of asthma.
BACKGROUND
Corticotropin-releasing hormone (CRH) is a major regulator of adrenocorticotropic hormone and the production of glucocorticoids by the adrenal gland. Abnormal regulation of CRH and endogenous glucocorticoids has been implicated in the pathogenesis of asthma.


OBJECTIVE
We postulated that CRH deficiency could increase asthma severity by disrupting hypothalamus-pituitary-adrenal axis function and the induction of glucocorticoids through inflammatory and physiologic stress. However, CRH is expressed by several types of immune cells and might be induced at sites of inflammation, where it has local immunostimulatory actions. Thus CRH deficiency could decrease asthma severity.


METHODS
To test these possibilities, we subjected CRH-knockout mice to an ovalbumin-induced airway inflammation protocol that mimics many features of asthma.


RESULTS
CRH-knockout mice had an increase in airway inflammation of approximately 80% to 300% and an increase in goblet cell hyperplasia of approximately 70% compared with wild-type mice. In contrast, IgE induction was unaffected by CRH deficiency. The increased inflammation in knockout mice was associated with increased tissue resistance, elastance, and hysteresivity. Levels of IL-4, IL-5, IL-13, RANTES, IFN-gamma, and eotaxin were all increased in knockout mice. Serum corticosterone levels were decreased in knockout mice and might account for some of the differences between knockout and wild-type mice.


CONCLUSIONS
We conclude that CRH deficiency disrupts endogenous glucocorticoid production and enhances allergen-induced airway inflammation and lung mechanical dysfunction in mice. Thus inherited or acquired CRH deficiency could increase asthma severity in human subjects.
Silverman
Eric S
ES
Physiology Program, Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115-6021, USA. esilverm@HSPH.harvard.edu
Breault
David T
DT
Vallone
Joseph
J
Subramanian
Srikanth
S
Yilmaz
Ayca D
AD
Mathew
Sheeba
S
Subramaniam
Venkat
V
Tantisira
Kelan
K
Pacák
Karel
K
Weiss
Scott T
ST
Majzoub
Joseph A
JA
D000485:Allergens / Q000009:adverse effects* / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000276:immunology* / Q000503:physiopathology; D016535:Bronchial Hyperreactivity / Q000276:immunology / Q000503:physiopathology; D003346:Corticotropin-Releasing Hormone / Q000172:deficiency* / Q000276:immunology*; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D023421:Models, Animal; D011014:Pneumonia / Q000276:immunology* / Q000503:physiopathology
D000485:Allergens; D003346:Corticotropin-Releasing Hormone