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Experiments analyzing the functions of nitric oxide (NO) donors during polymorphonuclear leukocyte (PMN) activity and comparing the anti-adhesive effects of NO donors on the immunoneutralization of three adhesion glycoproteins, P-selectin, intercellular adhesion molecule-1 and CD11/CD18 reveal that NO donors significantly inhibit PMN adhesion to the postcapillary venules but not the rolling of PMNs. Anti-P-selectin antibody suppresses the flux of PMN rolling while anti-CD18 monoclonal antibody IB4 inhibits leukocyte adhesion as do NO donors. The increase in the amount of rolling PMN and the adhesion of PMN depend on P-selectin and CD18, respectively, to mediate the onset of PMN infiltration.

Ischemic reperfusion of small bowels initiates mast cell stimulation and degranulation by oxidants, leading to elevated granulocyte infiltration and mucosal dysfunction. An increase in plasma rat mast cell protease II levels, myeloperoxidase activity and epithelial permeability are caused by ischemic reperfusion. Platelet-activating factor, which is a mast cell-derived mediator, contributes to granulocyte infiltration but is not involved in epithelial permeability changes due to reperfusion.

An analysis of molecular processes related to superoxide-induced leukocyte-endothelial cell interactions in vivo reveals that the enhanced leukocyte flux, induced by superoxide, is mediated by P-selectin. Leukocyte adhesion is modulated by platelet activating factor (PAF) and adhesion molecule CD18. CD18, and not P-selectin, may be responsible for a decline in leukocyte rolling velocity, induced by PAF.

Studies to evaluate the role of mast cells and mediators from mast cells in the increased epithelial permeability, accompanying synthesis of nitric oxide in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME), showed that epithelial permeability enhanced significantly due to L-NAME while mucosal permeability was reduced by two mast cell stabilizers. L-NAME-treated animals exhibited increased levels of rat mast cell protease II activity.

Nitric oxide is a homeostatic regulator of microvascular permeability in the feline small intestine, acting through specific activation of cystosolic guanylate cyclase and increased guanosine 3'5'-cyclic monophosphate (cGMP) levels. The atrial natriuretic factor causes changes in the intestinal microvascular permeability that are unrelated to cGMP levels. This is possibly due to the absence of membrane-associated guanylase cyclase in intestinal microcirculation.

A study was conducted to test whether the theory that the antiadhesive characteristics of nitric oxide (NO) are connected to superoxide production is correct by utilizing hypoxanthine-xanthine oxidase infusion to produce superoxide-dependent rolling and adhesion. It is possible for NO to act as an antiadhesion molecular in vivo, and the antiadhesion characteristics of NO are connected to its capacity to inactivate the superoxide anion.

Reperfusion of the postischemic intestine causes impairment of mucosal activity, which is ametiorated by nitric oxide synthesis-suppression. Exogenous nitric oxide sources are capable of blocking mucosal barrier destruction, as was revealed in feline intestinal ischemic studies. This is observed in SIN-1, AS-754, nitroprusside and exogenous L-arginine. Intestinal blood flow does not affect nitric oxide amelioration of mucosal dysfunction.

The role of nitric oxide (NO) in intestinal barrier function following ischemia-reperfusion was investigated. The study protocol involved intra-arterial infusion of the NO synthesis inhibitor N(super G)-nitro-L-arginine methyl ester in autoperfused cat ileum segments after ischemia-reperfusion. The results showed that NO synthesis is necessary in minimizing dysfunction of the mucosal and microvascular barrier due to intestinal ischemia-reperfusion. Inactivation of NO synthesis aggravates tissue injury.

Abstract Background Fever is one of the most commonly observed abnormal signs in patients with critical illness. However, there is a paucity of evidence to guide the management of febrile patients without acute brain injury and little is known about the biologic response to treatment of fever. As such, observational studies suggest that the treatment of fever is inconsistent. This pilot clinical trial will assess the safety and feasibility of treating febrile critically ill adult patients with an aggressive versus a permissive temperature control strategy. The biologic response to these two different temperature control strategies will also be assessed through analysis of a panel of inflammatory mediators. Findings The study population will include febrile adult patients admitted to one of two general medical-surgical intensive care units (ICUs) in Calgary, Alberta, Canada. Patients will be randomized to either an aggressive or permissive fever treatment strategy. The aggressive group will receive acetaminophen 650 mg enterally every 6 hours upon reaching a temperature ≥ 38.3°C and external cooling will be initiated for temperatures ≥ 39.5°C, whereas the permissive group will receive acetaminophen 650 mg every 6 hours upon reaching a temperature ≥ 40.0°C and external cooling for temperatures ≥ 40.5°C. The study will take place over 12 months with the goal of enrolling 120 patients. The primary outcome will be 28-day mortality after study enrolment, with secondary outcomes that will include markers of feasibility (e.g. the enrolment rate, and the number of protocol violations), and levels of select inflammatory and anti-inflammatory mediators. Discussion Results from this study will lead to a better understanding of the inflammatory effects of anti-pyretic therapy and will evaluate the feasibility of a future clinical trial to establish the best treatment of fever observed in nearly one half of patients admitted to adult ICUs. Trial Registration ClinicalTrials.gov: NCT01173367