The nitric oxide dependence of cutaneous microvascular function to independent and combined hypoxic cold exposure

Hypoxic modulation of nitric oxide (NO) production pathways in the cutaneous microvasculature and its interaction with cold-induced reflex vasoconstriction, independent of local cooling, have yet to be identified. This study assessed the contribution of NO to nonglabrous microvasculature perfusion during hypoxia and whole body cooling with concomitant inhibition of NO synthase [NOS; via NG-nitro-l-arginine methyl ester (l-NAME)] and the nitrite reductase, xanthine oxidase (via allopurinol), two primary sources of NO production. Thirteen volunteers were exposed to independent and combined cooling via water-perfused suit (5°C) and normobaric hypoxia (FIO2, 0.109 ± 0.002). Cutaneous vascular conductance (CVC) was assessed across four sites with intradermal microdialysis perfusion of 1) lactated Ringers solution (control), 2) 20 mmol l-NAME, 3) 10 µmol allopurinol, or 4) combined l-NAME/allopurinol. Effects and interactions were assessed via four-way repeated measures ANOVA. Independently, l-NAME reduced CVC (43%, P < 0.001), whereas allopurinol did not alter CVC (P = 0.5). Cooling decreased CVC (P = 0.001), and the reduction in CVC was consistent across perfusates (~30%, P = 0.9). Hypoxia increased CVC (16%, P = 0.01), with this effect abolished by l-NAME infusion (P = 0.04). Cold-induced vasoconstriction was blunted by hypoxia, but importantly, hypoxia increased CVC to a similar extent (39% at the Ringer site) irrespective of environmental temperature; thus, no interaction was observed between cold and hypoxia (P = 0.1). l-NAME restored vasoconstriction during combined cold-hypoxia (P = 0.01). This investigation suggests that reflex cold-induced cutaneous vasoconstriction acts independently of NO suppression, whereas hypoxia-induced cutaneous vasodilatation is dependent on NOS-derived NO production

Regulation of the expression of chaperone gp96 in macrophages and dendritic cells

The chaperone function of the ER-residing heat shock protein gp96 plays an important role in protein physiology and has additionally important immunological functions due to its peptide-binding capacity. Low amounts of gp96 stimulate immunity; high quantities induce tolerance by mechanisms not fully understood. A lack of gp96 protein in intestinal macrophages (IMACs) from Crohn`s disease (CD) patients correlates with loss of tolerance against the host gut flora, leading to chronic inflammation. Since gp96 shows dose-dependent direction of immunological reactions, we studied primary IMACs and developed cell models to understand the regulation of gp96 expression. Induction of gp96-expression was higher in in vitro differentiated dendritic cells (i.v.DCs) than in in vitro differentiated macrophages (i.v.MACs), whereas monocytes (MOs) expressed only low gp96 levels. The highest levels of expression were found in IMACs. Lipopolysaccharide (LPS), muramyl dipeptide (MDP), tumour necrosis factor (TNF), and Interleukin (IL)-4 induced gp96-expression, while IL12, IL-17, IL-23 and interferon (IFN)-γ were not effective indicating that Th1 and Th17 cells are probably not involved in the induction of gp96. Furthermore, gp96 was able to induce its own expression. The ER-stress inducer tunicamycin increased gp96-expression in a concentration- and time-dependent manner. Both ulcerative colitis (UC) and CD patients showed significantly elevated gp96 mRNA levels in intestinal biopsies which correlated positively with the degree of inflammation of the tissue. Since gp96 is highly expressed on the one hand upon stress induction as during inflammation and on the other hand possibly mediating tolerance, these results will help to understand the whether gp96 plays a role in the pathophysiology of inflammatory bowel disease (IBD)

Becoming urban: sitework from a moss-eye view

Discussing an urban walking event, “Moss-eye view”, held in the City of London as part of the This Is Not A Gateway festival (October 2010), this paper considers the ways in which cities may be understood from the view of more-than-human processes and incorporations. The walk explores how distinct insights emerge into ways of ‘becoming urban’ by attending to organisms, environments, and forms of sitework that are not typically foregrounded in the usual economies of the City of London. Moss incorporates the material effects of urban ecologies across time and space, and thus forms a process of bio-indication in the city, capturing pollutants and making resources available for other organisms. Mosses in the city might be studied as sentient, more-than-human exchangers of and participants in urban energies, and as in-between and peripheral organisms that connect up sites by working across material, affective, political, socionatural, and imaginative registers. It is argued that the “Moss-eye view” walking event is a form of research that opens up infra-urban practices for understanding cities through alternative associations and incorporations of urban life