In the late 1960s, several labatories identified guanylyl cyclase (GC) as the cGMP‐producing enzyme. Subsequently, two different types of GC were described that differed in their cellular localization. Primarily found in the cytosol, nitric oxide (NO)‐sensitive guanylyl cyclase (NO‐GC) acts as receptor for the signalling molecule NO, in contrast the membrane‐bound isoenzyme is activated by natriuretic peptides. The lung compared with other tissues exhibits the highest expression of NO‐GC. The enzyme has been purified from lung for biochemical analysis. Although expressed in smooth muscle cells (SMCs) and in pericytes, the function of NO‐GC in lung, especially in pericytes, is still not fully elucidated. However, pharmacological compounds that target NO‐GC are available and have been implemented for the therapy of pulmonary arterial hypertension. In addition, NO‐GC has been suggested as drug target for the therapy of asthma, acute respiratory distress syndrome and pulmonary fibrosis. LINKED ARTICLES This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc

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Pulmonary fibrosis is a chronic and progressive disease with limited therapeutic options. Nitric oxide (NO) is suggested to reduce the progression of pulmonary fibrosis via NO-sensitive guanylyl cyclase (NO-GC). The exact effects of NO-GC during pulmonary fibrosis are still elusive. Here, we used a NO-GC knockout mouse (GCKO) and examined fibrosis and inflammation after bleomycin treatment. Compared to wildtype (WT), GCKO mice showed an increased fibrotic reaction, as myofibroblast occurrence (p = 0.0007), collagen content (p = 0.0006), and mortality (p = 0.0009) were significantly increased. After fibrosis induction, lymphocyte accumulations were observed in the lungs of GCKO but not in WT littermates. In addition, the total number of immune cells, specifically lymphocytes (p = <0.0001) and neutrophils (p = 0.0047), were significantly higher in the bronchoalveolar lavage fluid (BALF) of GCKO animals compared to WT, indicating an increased inflammatory response in the absence of NO-GC. The pronounced fibrotic response in GCKO mice was paralleled by significantly increased levels of transforming growth factor β (TGFβ) in BALF (p = 0.0207), which correlated with the total number of immune cells. Taken together, our data show the effect of NO-GC deletion in the pathology of lung fibrosis and the effect on immune cells in BALF. In summary, our results show that NO-GC has anti-inflammatory and anti-fibrotic properties in the murine lung, very likely by attenuating TGFβ-mediated effects.

Background: The cyclic nucleotides cAMP and cGMP inhibit platelet activation. Results: We extended an older model and systematically integrated drugs as external stimuli. Data driven modeling allowed us to design models that provide a quantitative output for quantitative input information. This relies on condensed information about involved regulation and modeling of pharmacological interventions by systematic optimization methods. By multi-experiment fitting, we validated our model optimizing the parameters of the model. In addition, we show how the output of the developed cGMP model can be used as input for a modular model of VASP phosphorylation and for the activity of cAMP and cGMP pathways in platelets. Conclusions: We present a model for cGMP signaling and VASP phosphorylation, that allows to estimate drug action on any of the inhibitory cyclic nucleotide pathways (cGMP, cAMP) and has been validated by experimental data.