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This effect was achieved due to the inhibition of myeloid-derived suppressor cells (Gr-1 + CD11b) and downregulation of IL-4R ? .

Consequently, it resulted in the restoration of the CD8 + T cell response.

NO-cGMP pathway has neuroprotective and antiapoptotic effects by increasing the level cGMP.

Intracellular accumulation of cGMP in different models of inflammation reduces production buy cheap silagra of proinflammatory cytokines and reduces oxidative stress [25]. [40] aimed to investigate the possible protective effects of sildenafil citrate on tissue integrity, oxidant–antioxidant status, and neutrophil infiltration to the inflamed organ in a rat model of bleomycin-induced lung fibrosis.

Treatment of animals with sildenafil (10 mg/kg subcutaneously for 14 days) was beneficial with regard to prevention of lipid peroxidation, cytokine (IL-1 ? and TNF- ? ) production, neutrophil accumulation, and myeloperoxidase (MPO) activation. [41] showed that sildenafil exerts anti-inflammatory effects in vitro in LPS-activated microglial cells by blocking the nuclear factor kappa-light-chain-enhancer of activated B cells (NF- ? B) and Mitogen Activated Protein Kinase (MAPK) activation. Sildenafil markedly inhibited iROS production induced by LPS, which may be partly due to MAPKs potent downregulation of the NADPH-derived iROS production [40].

[42] found that sildenafil treatment in a murine model of EAE resulted in changes in the expression of several genes implicated in responses to stress and inflammation, as well as genes involved in cytoskeleton reorganization and wound healing.

Sildenafil caused 2.5-fold increase of mRNA expression of inflammation-related genes chitinase 3-like 3 (YM-1) protein secreted by peritoneal macrophages. On the other hand, microglia/macrophages ionized calcium-binding adapter molecule-microglia activation marker (Iba-1) was decreased. These results suggest that sildenafil promotes a switch from the M1 proinflammatory (M1) to the anti-inflammatory (M2) phenotype macrophages [42].

Macrophages

generated

It also downregulates inflammation in vitro and in various animal models.

NO may act as an endogenous activator of AMPK and in an opposite way inactivates NF ? B by phosphorylation of inhibitor k binding ? (IK ?? ). The study proved that sildenafil exerts its anti-inflammatory effect probably through AMPK-eNOS/NO-NF ? B signaling.

Sildenafil can also act directly through cGMP and indirectly by PKA on NF ? B inhibition [45]. Administration of sildenafil reduced the expression of IL-1 ? and TNF- ? and increased the level of anti-inflammatory cytokine IL-10 [41, 45].

There is ample evidence to indicate the role of CCR-2 (monocyte chemoattractant protein 1-MCP-1-receptor-CCl-2) in tissue repair after injury and increased neurogenesis due buy cheap silagra to its chemotactic property in neural precursor cells [46]. [47] suggested that increase of CCR-2/MCP-1 is associated with the stimulation cGMP-PKG signaling induced by sildenafil, and it can stimulate protective M2 phagocytic phenotype of microglia.

This study also demonstrated that expression of extracellular metalloproteinase-9 (MMP-9) is increased after sildenafil treatment.

Most MMPs are secreted as inactive proteins which buy cheap silagra are activated when cleaved by extracellular proteinases.

However, it has been proposed that MMPs have a role in modulating different physiological processes, such as reproduction, angiogenesis, bone development, apoptosis, and cell migration.

reported that sildenafil facilitated vascular remodeling by enhancement of MMP-9 expression [47].

Lung ischemia/reperfusion (I/R) injury plays an important role in outcome of organ transplantation. [48] in studies on rats suggested that watering with saline and sildenafil (10 mg/kg) 3 h before the operation improved lung I/R injury by decreasing the production of IL-6 and TNF- ? .

It has been shown that pretreatment with sildenafil normalizes TNF- ? and IL-6 levels in lung tissue, which suggests that pretreatment with sildenafil alleviated inflammation in early reperfusion injury.

Similar findings were reported recently by Zahran et al.

[49], after investigation of rats renal ischemia/reperfusion injury. Watering rats orally with SC 1 mg/kg 60 min before anesthesia resulted in activation of antioxidant genes (Nrf2, HO-1 and NQO-1-quinone oxidoreductase) and antiapoptotic gene (Bcl-2) and attenuation of proinflammatory cytokines (TNF- ? , IL-1 ? ) as well as ICAM-1.

Expression of genes was evaluated in ischemic kidney tissue after nephrectomy. Effects of sildenafil were maximal after 2 days from SC administration.

The Effects of Sildenafil on the Lymphocytes Subpopulations of Healthy Human Blood Donors.

The only data of the effects of sildenafil on healthy human lymphocytes in vitro comes from Pifarre et al.

[30] studies on human T regulatory cells.Cocultures of T effector cells and T reg cells (0.25 : 1 and 0.5 : 1 ratio) isolated from healthy donor peripheral blood showed that sildenafil at the 10 ? M concentration influenced the ability of Tregs to downregulate T effector cell proliferation.

Moreover, expression of Treg transcription factor Foxp3 was increased, suggesting that upregulation of Tregs is involved in T effector cell deactivation.

The Effects of Sildenafil on the Immune System in Patients Treated with Sildenafil. The influence of sildenafil on the TNF- ? level, Treg, and NK activity in patients with recurrent abortion was reported. [50] found that sildenafil significantly reduced peripheral blood NK activity in 38 women with natural and after in vitro fertilization (IF) recurrent abortion.

Sildenafil was administered intravaginally during the proliferative phase of the menstrual cycle for 3 or 6 days.

NK cells activity was also investigated in in vitro cultures of mononuclear cells (MNC) of the patients and the control group.

Sildenafil added at the 10 ? g/mL concentration to the culture of MNC of healthy women reduced NK cell activity [50].

Determination of serum TNF- ? level revealed a tendency to increase after sildenafil therapy [51].

These results were in contrast with the findings of El-Far et al.

In the latter study, the percentages of CD3 + CD56 + CD161 + NKT cells and TNF- ? positive T cells were greatly reduced after sildenafil intravaginal administration (25 mg/4 times a day for 24 days). The differences could be explained by different dosing of the drug.

Preeclampsia is a disorder of pregnancy characterized by high blood pressure and level of protein in urine, due to endothelial dysfunction and is a primary cause of maternal morbidity.

It affects 2–8% of pregnancies worldwide, and, if not treated, leads to eclampsia.

Complications include aspiration pneumonia, cerebral hemorrhage, kidney failure, and cardiac arrest [53]. The vascular endothelial grow factors (VEGFs) family of proteins and their receptors are thought to be key contributors to this disease. It is believed that high level of VEGF and placental growth factor (PLGF) are involved in vascular remodeling of cytotrophoblast. The VEGF-receptor-1 is denoted as soluble fms-like tyrosine kinase-1 (sFlt-1) as it belongs to fms related tyrosine kinase family.

Placenta of pregnant women with preeclampsia produces high levels of sFlt-1.

sFlt-1 binds to free VEGF and PLGF, inactivates them, and makes them unavailable for proper signaling [54]. Advanced glycation end-products (AGEs) represent the molecular complexes generated as a result of nonenzymatic reactions of carbohydrates and oxidized lipid with proteins.

These reactions lead to the irreversible cross-linking of proteins and, as a consequence, loss of protein structure and function. Previous studies demonstrated that serum AGEs in preeclamptic women were significantly higher than in healthy women.

Accumulation of AGEs may induce oxidative injury and vascular perturbation in placental bed, leading to preeclampsia [55]. showed that AGEs contribute to elevation of sFlt-1.

The study was conducted on JEG-3 cell line established from choriocarcinoma that was shown to retain trophoblastic cell-like characteristics. They observed that AGEs-BSA increased sFlt-1 mRNA expression and protein release as well as

increasing

In addition, sildenafil induced apoptosis of the B-CLL cells in caspase 3-dependent way in vitro.

It has been shown that IL-4 abrogated the effect of sildenafil.

Interestingly, there was no killing effect of sildenafil on normal B-cells. [58] reported similar findings in 5 patients suffering from Waldenstrom’s macroglobulinemia (WM) and erectile dysfunction. WM tumor cells were also culture-sorted with sildenafil at pharmacologically relevant levels and apoptosis was demonstrated in tumor cells from all 5 patients.

Possibly, the modulating effect of sildenafil on lymphocyte subpopulations and humoral immune responses is also mediated by the synthesis and release of cytokines [21, 22, 59]. Sildenafil improves the condition of patients with Reynaud’s phenomenon and helps wound healing in scleroderma by inhibiting the TGF- ? –Rho kinase pathway. TGF- ? acts as an antiproliferative factor in normal epithelial cells and at the early stages of oncogenesis [60, 61].

Some cells which secrete TGF- ? also have receptors for this cytokine, a phenomenon known as autocrine signaling.

Cancer cells increase production of TGF- ? , which also affects the surrounding cells. The Rho GTPases are involved in numerous signal transduction pathways and act as regulators of the actin cytoskeleton, cell motility, and transcription. They are associated with progression to malignancy in several types of cancer. The Rho GTPases are molecular switches which remain inactive when GDP bound and active when GTP bound, and they expand their signals through interaction with numerous downstream signaling effectors [62–64].

In this way it is possible that sildenafil affects oncogenesis. [65] suggested that sildenafil inhibits RhoA/Rho kinase-dependent functions in the pulmonary artery through enhanced RhoA phosphorylation and cytosolic sequestration by GDP.

The inhibition of intracellular events downstream of RhoA thus participates in the beneficial effect of sildenafil in pulmonary hypertension. [66] described a patient with multiple sclerosis who developed severe PAH after treatment with IFN- ? -1a.

Sildenafil reversed the detrimental effect of IFN- ? on the cardiovascular system. Reduced NO production is correlated with poor wound healing in diabetic patients.

Sildenafil improved the production of NO in diabetic subjects.

Chronic administration of sildenafil in diabetic patients was associated with an increase in nitrite/nitrate levels and improved markers of vascular inflammation with a decrease of endothelin-1, IL-6 level, lower expression of integrins, including intracellular adhesion molecules (ICAM), and vascular adhesion molecules (VCAM). Furthermore, the effect of sildenafil therapy was sustained after one month from withdrawal of the drug [67, 68].

A growing body of evidence shows that sildenafil exerts immunomodulatory effects. Its positive action was demonstrated in treating severe autoimmune diseases and cancer.

In addition, anti-inflammatory and antiaggregation effects of sildenafil have also been reported.

In tumor-bearing mice, the inhibition of PDE5 activity with sildenafil prolonged the survival of the animals through augmentation of antitumor immunity. Daily sildenafil treatment from EAE symptom onset prevented further clinical deterioration and improved neurogenesis.

Sildenafil decreased the levels of proinflammatory cytokines, including TNF- ? , IL-1, and reduced NK cells activity, and enhanced the action of regulatory T cells.

Sildenafil markedly inhibited iROS production induced by LPS.

Type 5 phosphodiesterase (PDE5) inhibitor increased endothelial cell cGMP and promoted angiogenesis by increasing the expression of VEGF. De novo blood vessel formation is essential for embryonic vascular development and for postnatal vascular homeostasis and wound healing.

Thus, the available data suggest that sildenafil could find use in the treatment of autoimmune, neurodegenerative, and cardiovascular diseases, as well as recurrent abortions.

However, the potential immunomodulatory effects of sildenafil in humans remain to be confirmed. B-CLL: B-cell chronic lymphocytic leukemia cGMP: Cyclic guanosine monophosphate ED: buy cheap silagra Erectile dysfunction GMP: Guanosine monophosphate IL: Interleukin NKT: Natural killer T-cells NO: Nitric oxide NOS: Nitric oxide synthase PDE-Is: Phosphodiesterase inhibitors PDEs: Phophodiesterases PKG: Protein kinase G ROS-Nrf2: Reactive oxygen species-nuclear erythroid 2-related factor 2 SC: Sildenafil citrate sGC: Soluble guanylate cyclase TGF- ? : Transforming growth factor- ? TNF- ? : Tumor necrosis factor- ? Treg: Lymphocyte T regulatory cells.

The authors declare that they have no competing interests.

This work was supported by a grant from National Science Centre, Poland (NSC), no.

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