Recent studies indicate that the abnormal microenvironment of tumors may play a critical role in carcinogenesis, including lung cancer. We comprehensively assessed the number of stromal cells, especially immune/inflammatory cells, in lung cancer and evaluated their infiltration in cancers of different stages, types and metastatic characteristics potential. Immunohistochemical analysis of lung cancer tissue arrays containing normal and lung cancer sections was performed. This analysis was combined with cyto-/histomorphological assessment and quantification of cells to classify/subclassify tumors accurately and to perform a high throughput analysis of stromal cell composition in different types of lung cancer. In human lung cancer sections we observed a significant elevation/infiltration of total-T lymphocytes (CD3 ) compared with healthy donor specimens. We observed all of these immune cell markers in different types of lung cancers including squamous cell carcinoma, adenocarcinoma, adenosquamous cell carcinoma, small cell carcinoma, papillary adenocarcinoma, metastatic adenocarcinoma, and bronchioloalveolar carcinoma. The numbers of all tumor-associated immune cells (except MUM1 + cells) in stage III cancer specimens was significantly greater than those in stage I samples. We observed substantial stage-dependent immune cell infiltration in human lung tumors suggesting that the tumor microenvironment plays a critical role during lung carcinogenesis. Strategies for therapeutic interference with lung cancer microenvironment should consider the complexity of its immune cell composition.

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Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary vascular resistance caused by endothelial dysfunction, inward vascular wall remodeling and severe loss of cross−sectional area of the precapillary pulmonary vessels. Asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and its metabolizing enzyme dimethylarginine dimethylaminohydrolase (DDAH) play important roles in endothelial dysfunction. We investigated whether a combined phosphodiesterase (PDE) 3 and 4 inhibitor ameliorates endothelial function by regulating the ADMA−DDAH axis. We investigated the effects of the PDE3/4 inhibitor tolafentrine in vitro on ADMA−induced apoptosis and DDAH expression in endothelial cells and in vivo on monocrotaline (MCT)−induced pulmonary hypertension in rats. Real−time PCR analysis, immunocytochemistry and PDE activity assays suggested high expression of isoforms PDE3 and 4 in endothelial cells. Further, treatment of endothelial cells with the PDE3/4 inhibitor tolafentrine significantly decreased ADMA−induced apoptosis, concomitantly with upregulation of DDAH2. Chronic nebulization of the PDE3/4 inhibitor significantly attenuated all MCT−induced hemodynamic abnormalities, vascular remodeling, and right heart hypertrophy. Interestingly, PDE3/4 inhibitor treatment reduced ADMA levels, elevated nitric oxide/cGMP levels, and augmented DDAH2 expression and activity. In addition, the PDE3/4 inhibitor suppressed apoptosis in endothelial cells and increased vascularization in the lung. Combined inhibition of PDE3 and 4 prevents the development of PAH and promotes endothelial regeneration by modulating DDAH2 expression and ADMA levels.This abstract is funded by: SFB 547 and Else−Kröner−Fresenius Foundation.

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