According to the World Health Organization millions of people worldwide suffer from respiratory diseases such as bronchial Asthma, Ideopathic Pulmonary Fibrosis (IPF) and Chronic Obstructive Pulmonary Disease (COPD) with COPD being the fourth leading cause of death. A persistent inflammatory response has been thought to be the reason for such pulmonary diseases to become chronic. The consequence is a remodeling of the airway tissue structure, where most pulmonary diseases share similar features like epithelial loss, smooth muscle cell (SMC) hyperplasia and hypertrophy, angiogenesis and a deposition of extracellular matrix (fibrosis). Inhaled bronchodilators and corticosteroids only help to decrease the severity of symptoms, but there is no strategy available known to prevent airway remodeling. Nitric oxide (NO), which is excessively generated under allergic airway inflammation, is known to modulate immune responses. In general NO acts via its receptor NO-sensitive guanylyl cyclase (NO-GC), thereby promoting cyclic guanosine monophosphate (cGMP) formation. Consequently, a modulatory role of NO-GC for immune responses is suggested. Furthermore, antifibrotic effects of cGMP by an inhibition of TGFβ-mediated myofibroblast activation have been described. To study the role of NO-GC1 in allergic inflammation and tissue remodeling we used NO-GC1 knockout mice (NO-GC1 k. o.) and sensitized and challenged them with ovalbumin. However, we found reduced allergic inflammation and Th2 response in these mice due to a shift in T-helper cells towards a Th1 phenotype. We suggest a reduced activity of phosphodiesterases in NO-GC k. o. mice, due to an increased intracellular cyclic adenosine monophosphate (cAMP) concentration in dendritic cells, to influence the Th1/Th2 balance. Despite the reduced allergic inflammation we found increased airway fibrosis in the k. o. mice as measured in lung sections stained for collagen. In order to identify the cell type responsible for the elevated tissue remodeling without influencing the immune response, we aim to specifically delete NO-GC1 in SMC, where NOGC-1 is predominantly expressed in the lungs. With the help of a tamoxifen-inducible Cre recombinase system we are able to delete NO-GC 1 specifically in αSMA-expressing cells (SMC, myofibroblasts) of adult mice. This way, the potential exacerbation of tissue remodeling due to a decreased cGMP forming capacity of SMCs and myofibroblasts can be investigated for different pulmonary disease models like chronic OVA-asthma and Bleomycin-induced IPF.
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