Oxygen radical generation of neutrophils: a reason for oxidative stress during marathon running?

Hematological parameters and blood markers that indicate oxidative stress, such as lipid peroxides (LPO), reduced and oxidized glutathione (GSH, GSSG), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), were measured in 18 marathon runners before, immediately after the race, and after 8 days of rest. In parallel, the oxygen radical generation of neutrophils (PMN) was measured by chemiluminescence in six randomly selected runners. After the race, a 4.4-fold enhanced PMN count and a 1.4-fold increased capacity to generate oxygen radicals of the PMN (2.20+/-0.38 vs. 3.12+/-0.69 arb. unit/10(6) cells) were found. Consequently, a 6.25-fold increased capacity to generate oxygen radicals of the post-run blood (7.26+/-1.3 vs. 45.40+/-10.3 arb. unit/ml blood) was calculated. This points to PMN as an important oxygen radical source established in the runners' blood, which could contribute to the oxidative stress indicated in the post-run blood by increased LPO (11.46+/-3.09 vs. 13.09+/-3.14 micromol/l plasma), GSSG (0.038+/-0.003 vs. 0.045+/-0. 005 mmol/l blood) and GSSG/GSH ratio (3.8+/-0.5 vs. 4.1+/-0.6%) and by decreased SOD (15.63+/-1.78 vs. 14.58+/-1.51 10(3)U/mmol Hb) and GSH-Px (485.1+/-107.1 vs. 434.9+/-101.7 U/mmol Hb). Despite the decline of the oxygen radical source during rest, the oxidative stress in the blood did not decrease in all runners.     

The oxysterol–CXCR2 axis plays a key role in the recruitment of tumor-promoting neutrophils

Tumor-infiltrating immune cells can be conditioned by molecules released within the microenvironment to thwart antitumor immune responses, thereby facilitating tumor growth. Among immune cells, neutrophils play an important protumorigenic role by favoring neoangiogenesis and/or by suppressing antitumor immune responses. Tumor-derived oxysterols have recently been shown to favor tumor growth by inhibiting dendritic cell migration toward lymphoid organs. We report that tumor-derived oxysterols recruit protumor neutrophils in a liver X receptor (LXR)–independent, CXCR2-dependent manner, thus favoring tumor growth by promoting neoangiogenesis and immunosuppression. We demonstrate that interfering with the oxysterol–CXCR2 axis delays tumor growth and prolongs the overall survival of tumor-bearing mice. These results identify an unanticipated protumor function of the oxysterol–CXCR2 axis and a possible target for cancer therapy.Tumor formation is the result of molecular alterations involving cellular regulators (Hanahan and Weinberg, 2011) as well as the ability of tumor cells to affect the tumor microenvironment by smoldering inflammation (de Visser et al., 2006; Mantovani et al., 2008) or even taking advantage of inflammation to grow and metastasize (Zitvogel et al., 2006; Grivennikov et al., 2010). Indeed, targeted therapies aimed to inhibit molecular alterations in tumor cells even though inducing antitumor responses have improved overall survival only slightly, indicating that antitumor strategies comprehensive of drugs targeting molecular as well as microenvironment alterations might be more effective (Vanneman and Dranoff, 2012). Tumor microenvironment is composed of various cell types, including tumor-associated macrophages endowed with phenotypes and functions of alternatively activated or M2 macrophages (i.e., expressing IL-10, TGF-β, ARG1, and mannose receptor; Mantovani and Sica, 2010), which have been shown to promote tumor initiation/formation through the induction of immune suppression, matrix remodeling, and angiogenesis (Murdoch et al., 2008), and the heterogeneous CD11b⁺Gr1⁺ myeloid cells, also termed myeloid-derived suppressor cells, comprising immature myeloid progenitors for neutrophils, monocytes, and DCs (Gabrilovich and Nagaraj, 2009). CD11b⁺Gr1⁺ myeloid cells are present in the tumor as well as in bone marrow, peripheral blood, and spleen of tumor-bearing mice (Bronte and Zanovello, 2005). In particular, the immature CD11b⁺Gr1⁺ bone marrow–derived cells, as well as the CD11b^highGr1^highLy6G⁺ neutrophils, have been recognized as playing an important protumorigenic role by promoting neoangiogenesis (Yang et al., 2004) through the release of MMP9 (Nozawa et al., 2006) and Bv8 (Shojaei et al., 2008), thus mediating refractoriness to anti-VEGF therapy (Shojaei et al., 2007a). Neutrophils have also been shown to suppress antitumor immune responses (Fridlender et al., 2009; De Santo et al., 2010).Several tumor-derived molecules induce immune suppression by affecting tumor-infiltrating immune cells (Vesely et al., 2011). Some of these molecules are intermediate or final products of the cellular metabolism, such as kynurenine, which, alone or together with the depletion of tryptophan, has been reported to promote T cell anergy (Mellor et al., 2003). Similarly, it has been shown that the increased metabolism of l-arginine by myeloid cells can result in the impairment of lymphocyte responses to tumor cells (Bronte and Zanovello, 2005). Other metabolic pathways have recently emerged as protumorigenic. Products of lipid and cholesterol metabolism have been demonstrated to damage the function of DC both in mouse and in human tumor models. As an example, lipid-loaded DCs are not able to effectively stimulate allogeneic T cells or to present tumor-associated antigens as the result of a reduced antigen processing capability (Herber et al., 2010).Liver X receptor (LXR) ligands, also named oxysterols, are involved in cholesterol homeostasis (Repa and Mangelsdorf, 2000) and in modulating immune responses (Bensinger and Tontonoz, 2008). The oxysterol 7α,25-HC, which is unable to activate LXRs, has recently been involved in B cell migration to follicles of lymphoid organ through the engagement of EBI2 receptor (Hannedouche et al., 2011; Liu et al., 2011). We have recently shown that LXR ligands/oxysterols are released by cancer cells and inhibit CCR7 expression on maturing DCs, therefore dampening DC migration to draining lymph nodes and antitumor immune responses (Villablanca et al., 2010). Indeed, tumor cells engineered to express the oxysterol inactivating enzyme sulfotransferase 2B1b (SULT2B1b; Fuda et al., 2007), fail to activate LXRs in vitro and are delayed or rejected when infused in immunocompetent mice (Villablanca et al., 2010). Whether tumor-derived LXR ligands/oxysterols are endowed with other protumorigenic functions, thus favoring the formation of hostile microenvironments for immune cells, remains elusive.Here, we show that tumor-derived oxysterols contribute to recruit neutrophils in a CXCR2-dependent manner within tumor microenvironment, thus favoring neoangiogenesis and/or immunosuppression and tumor growth. Importantly, we show that oxysterol inactivation, as well as CXCR2 inactivation, controls tumor growth, thus identifying a new protumor role of oxysterols and a new therapeutic target for cancer patients.     

Is there a role for remote ischaemic postconditioning in cardiopulmonary resuscitation?

Cardiac arrest causes whole body ischaemic injury and cellular death. Successful cardiopulmonary resuscitation (CPR) can subsequently lead to a global reperfusion phenomenon with a paradoxically increased rate of cellular death. Interventions that decrease the ischaemia-reperfusion injury may be useful in the treatment of these patients. Remote ischaemic postconditioning with transient limb ischaemia is feasible in cardiac arrest patients. This article discusses the concept of ischaemic pre- and postconditioning and its potential use in patients during CPR and after return of a spontaneous circulation.     

Treatment of inflammatory bowel disease: a role for hypnotherapy?

Fifteen patients with severe or very severe inflammatory bowel disease on corticosteroids but not responding to medication received 12 sessions of "gut-focused hypnotherapy" and were followed up for a mean duration of 5.4 years with disease severity being graded as remission, mild, moderate, severe, or very severe. Two patients (13.4%) failed to respond and required surgery. At follow-up for the remaining 13 patients, 4 (26.6%) were in complete remission, 8 (53.3%) had mild severity, and 1 (6.7%) was moderately severe. Quality of life became good or excellent in 12 (79.9%). Corticosteroid requirements dramatically declined with 60% of patients stopping them completely and not requiring any during follow-up. Hypnotherapy appears to be a promising adjunctive treatment for inflammatory bowel disease and has steroid sparing effects. Controlled trials to clearly define its role in this disease area are justified.     

Regulation of Aβ pathology by beclin 1: a protective role for autophagy?

The amyloid beta (Abeta) peptide is thought to be a major culprit in Alzheimer disease (AD), and its production and degradation have been intensely investigated. Nevertheless, it remains largely unknown how Abeta pathology is modulated by the autophagy pathway. The study by Pickford and colleagues in this issue of the JCI shows that beclin 1, a multifunctional protein that also plays an important role in the autophagy pathway, affects some aspects of Abeta pathology in aged but not young transgenic mice expressing amyloid precursor protein (APP) (see the related article beginning on page 2190). These findings further support the notion that modulation of autophagy, in this case through beclin 1, may represent a novel therapeutic strategy for AD.     

Pro-healing drug-eluting stents: a role for antioxidants?

Current strategies to lower the incidence of ISR (in-stent restenosis) following PCI (percutaneous coronary intervention) are aimed at modifying arterial healing after stent injury. This can impair endothelial recovery and render the vessel prone to acute thrombosis. As early restoration of endothelial integrity inhibits neointimal growth and thrombosis, alternative approaches which encourage this process may provide a more effective long-term result after PCI. Oxidative stress is enhanced after PCI and participates in the regulation of endothelial regeneration and neointimal growth. Moreover, evidence suggests antioxidants improve re-endothelialization and inhibit ISR. By promoting, rather than blocking, the healing process, antioxidant and other therapies may offer an alternative or additional approach over the antiproliferative approaches common to many current devices.