The present study provides direct evidence that exposure to LPS results in induction of iNOS and SOD associated with noradrenaline hyporeactivity, while increased NO is only measured when l-arginine is present. A catalase-sensitive mechanism and release of NO from N-acetylcysteine-sensitive stores could also contribute to the vascular hyporeactivity.

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SUMMARYHypoxic pulmonary vasoconstriction (HPV) is an adaptive response that diverts pulmonary blood flow from poorly ventilated and hypoxic areas of the lung to better ventilated parts, matching blood perfusion to ventilation. HPV is an ancient and highly conserved response expressed in the respiratory organs of all vertebrates. However, the underlying mechanism and the role of the endothelium remain elusive. Isolated intrapulmonary arteries (internal diameter <346·μm) from the American alligator Alligator mississippiensis were mounted in microvascular myographs for isometric tension recording. Resting vessels and vessels contracted with either serotonin (5-HT) or endothelin-1 (ET-1) were exposed to sustained (45·min) hypoxia (P O 2<5·mmHg). In ET-1-contracted vessels, hypoxia induced a monophasic, sustained and fully reversible constriction, which was independent of the endothelium. In relaxed or in 5-HT-contracted vessels, hypoxia did not cause constriction. The effects of ET-1, ET A and ET B as well as the general ET-receptor antagonist were studied. ET-1 caused a contraction of the pulmonary arteries through stimulation of ET A -receptors. ET A and ET B immunoreactive staining revealed the location of both receptors in the smooth muscle layer and of ET B receptors in the endothelium. In conclusion, because precontraction with serotonin did not facilitate HPV, the required precontraction in alligators seems specific to ET-1, which implies that ET-1 plays an important permissive role for the HPV response in alligators.

BackgroundSystemic inflammation, diagnostically ascribed by measuring serum levels of the acute phase reactant C-reactive protein (CRP), has consistently been correlated with poor outcomes across cancer types. CRP exists in two structurally and functionally distinct isoforms, circulating pentameric CRP (pCRP) and the highly pro-inflammatory monomeric isoform (mCRP). The aim of this pilot study was to map the pattern of mCRP distribution in a previously immunologically well-defined colon cancer (CC) cohort and explore possible functional roles of mCRP within the tumor microenvironment (TME).MethodsFormalin-fixed, paraffin-embedded (FFPE) tissue samples from 43 stage II and III CC patients, including 20 patients with serum CRP 0-1 mg/L and 23 patients with serum CRP &gt;30 mg/L were immunohistochemically (IHC) stained with a conformation-specific mCRP antibody and selected immune and stromal markers. A digital analysis algorithm was developed for evaluating mCRP distribution within the primary tumors and adjacent normal colon mucosa.ResultsmCRP was abundantly present within tumors from patients with high serum CRP (&gt;30 mg/L) diagnostically interpreted as being systemically inflamed, whereas patients with CRP 0-1 mg/L exhibited only modest mCRP positivity (median mCRP per area 5.07‰ (95%CI:1.32-6.85) vs. 0.02‰ (95%CI:0.01-0.04), p&lt;0.001). Similarly, tissue-expressed mCRP correlated strongly with circulating pCRP (Spearman correlation 0.81, p&lt;0.001). Importantly, mCRP was detected exclusively within tumors, whereas adjacent normal colon mucosa showed no mCRP expression. Double IHC staining revealed colocalization of mCRP with endothelial cells and neutrophils. Intriguingly, some tumor cells also colocalized with mCRP, suggesting a direct interaction or mCRP expression by the tumor itself.ConclusionOur data show that the pro-inflammatory mCRP isoform is expressed in the TME of CC, primarily in patients with high systemic pCRP values. This strengthens the hypothesis that CRP might not only be an inflammatory marker but also an active mediator within tumors.