Transforming growth factor-beta expression and signaling in the conducting airways of the rhesus macaque during postnatal development and in response to allergic airway disease

Airway development and maintenance of normal function following development are dependent upon balances between signaling molecules and the cellular interactions they regulate. Transforming growth factor (TGF)-beta is believed to be critical in airway development, homeostasis and disease. TGF-beta expression has been characterized during prenatal development, but not during the postnatal period, when a large portion of airway development takes place. Furthermore, little is known regarding TGF-beta expression in airway disease during the postnatal period. The rationale for this research was to first define the postnatal expression of TGF-beta within the airways of the rhesus macaque, a species whose development closely resembles that of children. In chapters 2 and 3, atopic infant monkeys were repeatedly exposed to an allergen and/or ozone to define alterations in airway expression of TGF-beta and TGF-beta signaling during the postnatal period. Finally, in chapter 4 the same model was used to determine if TGF-beta expression and signaling are restored following a modified 6 month recovery period. Each study used morphometric approaches to define specific airway regions which were then compared for immunohistochemical localization of TGF-beta1 and TGF-beta 2, and quantitation of pSmad 2/3, a downstream TGF-beta signaling molecule, using the optical dissector approach.;We conclude that: (1) TGF-beta3 is an active participant in the postnatal developmental of the airways, (2) postnatal airway expression of TGF-beta and TGF-beta signaling are significantly impacted by asthma and (3) alterations in expression persist following a modified recovery period.;We found that during postnatal development: (1) TGF-beta1 and -beta2 are expressed at all levels of the airways, (2) each has a unique pattern of expression, and (3) expression correlates with times during the postnatal period when development is most active and with sites within the airways where development is most pronounced. In atopic animals challenged with allergen and/or ozone, we found that the expression of TGF-beta 2 is increased within all levels of the airways and is associated with increased TGF-beta signaling. Finally, in animals allowed a 6 month recovery period, TGF-beta2 expression and signaling remained increased in allergen (+/- ozone) recovery groups whereas ozone recovery animals returned to a more normal phenotype.