抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, through a hitherto unrecognized metabolic route -- namely, the L-arginine-nitric oxide pathway1–8. The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure. In the central nervous system nitric oxide is a neurotransmitter that underpins several functions, including the formation of memory. . . .

The L-Arginine-Nitric Oxide Pathway

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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Nitric Oxide and Peroxynitrite in Health and Disease

Nitric oxide contrasts with most intercellular messengers because it diffuses rapidly and isotropically through most tissues with little reaction but cannot be transported through the vasculature due to rapid destruction by oxyhemoglobin. The rapid diffusion of nitric oxide between cells allows it to locally integrate the responses of blood vessels to turbulence, modulate synaptic plasticity in neurons, and control the oscillatory behavior of neuronal networks. Nitric oxide is not necessarily short lived and is intrinsically no more reactive than oxygen. The reactivity of nitric oxide per se has been greatly overestimated in vitro because no drain is provided to remove nitric oxide. Nitric oxide persists in solution for several minutes in micromolar concentrations before it reacts with oxygen to form much stronger oxidants like nitrogen dioxide. Nitric oxide is removed within seconds in vivo by diffusion over 100 microns through tissues to enter red blood cells and react with oxyhemoglobin. The direct toxicity of nitric oxide is modest but is greatly enhanced by reacting with superoxide to form peroxynitrite (ONOO-). Nitric oxide is the only biological molecule produced in high enough concentrations to out-compete superoxide dismutase for superoxide. Peroxynitrite reacts relatively slowly with most biological molecules, making peroxynitrite a selective oxidant. Peroxynitrite modifies tyrosine in proteins to create nitrotyrosines, leaving a footprint detectable in vivo. Nitration of structural proteins, including neurofilaments and actin, can disrupt filament assembly with major pathological consequences. Antibodies to nitrotyrosine have revealed nitration in human atherosclerosis, myocardial ischemia, septic and distressed lung, inflammatory bowel disease, and amyotrophic lateral sclerosis.

Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.

The acute respiratory distress syndrome is a common, devastating clinical syndrome of acute lung injury that affects both medical and surgical patients. Since the last review of this syndrome appeared in the Journal, 1 more uniform definitions have been devised and important advances have occurred in the understanding of the epidemiology, natural history, and pathogenesis of the disease, leading to the design and testing of new treatment strategies. This article provides an overview of the definitions, clinical features, and epidemiology of the acute respiratory distress syndrome and discusses advances in the areas of pathogenesis, resolution, and treatment. Historical Perspective and Definitions . . .

/pdf/the-acute-respiratory-distress-syndrome-4dksnctehq.pdf

The acute respiratory distress syndrome

Background: High dose (≥80 parts-per-million[ppm]) inhaled nitric oxide (NO) has antimicrobial effects. We designed a trial to test the preventive effects of high dose NO on coronavirus disease (COVID-19) in healthcare providers working with COVID-19 patients. The study was interrupted prematurely due to the introduction of COVID-19 vaccines for healthcare professionals. We thereby present data on safety and feasibility of breathing 160 ppm NO using two different NO sources, namely pressurized nitrogen/NO cylinders (iNO) and electric NO generators (eNO).Methods: Nitric oxide gas was inhaled at 160 ppm in air for 15 minutes twice a day, before and after each work shift, over 14 days to healthcare providers (NCT04312243). During NO administration vital signs were continuously monitored. Safety was assessed by measuring transcutaneous methemoglobinemia (SpMet) and the inhaled nitrogen dioxide (NO2) concentration.Results: 12 healthy healthcare professionals received a collective total of 185 administrations of high dose NO (160 ppm) for 15 minutes twice daily. 171 doses were delivered by iNO and 14 doses by eNO. During NO administration SpMet increased similarly in both groups (p=.82). Methemoglobin decreased in all subjects at five minutes after discontinuing NO administration. Inhaled NO2 concentrations remained between 0.70 [0.63-0.79] and 0.75 [0.67-0.83] ppm in the iNO group and between 0.74 [0.68-0.78] and 0.88 [0.70-0.93] ppm in eNO group. During NO administration peripheral oxygen saturation and heart rate did not change. No adverse events occurred.Conclusion: This pilot study testing high dose inhaled NO (160 ppm) for 15 minutes twice a day using eNO seem feasible and similarly safe when compared with iNO.

http://rc.rcjournal.com/content/respcare/early/2021/08/19/respcare.09308.full.pdf

High-Dose Nitric Oxide From Pressurized Cylinders and Nitric Oxide Produced by an Electric Generator From Air.

Effects of inhaled nitric oxide and l-name on intrapulmonary shunting in an ovine lavage ards model

Background: Sepsis is associated with an impaired pulmonary vasodilator response to inhaled nitric oxide (NO). A combination of NO and other inflammatory mediators appears to be responsible for endotoxin-induced pulmonary vascular hyporesponsiveness to inhaled NO. The authors investigated whether scavengers of reactive oxygen species could preserve inhaled NO responsiveness in endotoxin-challenged mice. Methods: The vasorelaxation to inhaled NO was studied in isolated, perfused, and ventilated lungs obtained from mice 16 h after an intraperitoneal challenge with saline or 50 mg/kg Escherichia coli lipopolysaccharide. In some mice, challenge with saline or lipopolysaccharide was followed by intraperitoneal administration of N-acetylcysteine, dimethylthiourea, EUK-8, or polyethylene glycol-conjugated catalase. Results: The pulmonary vasodilator response of U46619-pre-constricted isolated lungs to ventilation with 0.4, 4, and 40 ppm inhaled NO in lipopolysaccharide-challenged mice was reduced to 32, 43, and 60%, respectively, of that observed in saline-challenged mice (P < 0.0001). Responsiveness to inhaled NO was partially preserved in lipopolysaccharide-challenged mice treated with a single dose of N-acetylcysteine (150 or 500 mg/kg) or 20 U/g polyethylene glycol-conjugated catalase (all P < 0.05 vs. lipopolysaccharide alone). Responsiveness to inhaled NO was fully preserved by treatment with either dimethylthiourea, EUK-8, two doses of N-acetylcysteine (150 mg/kg administered 3.5 h apart), or 100 U/g polyethylene glycol-conjugated catalase (all P < 0.01 vs. lipopolysaccharide alone). Conclusions: When administered to mice concurrently with lipopolysaccharide challenge, reactive oxygen species scavengers prevent impairment of pulmonary vasodilation to inhaled NO. Therapy with scavengers of reactive oxygen species may provide a means to preserve pulmonary vasodilation to inhaled NO in sepsis-associated acute lung injury.

Radical scavengers protect murine lungs from endotoxin-induced hyporesponsiveness to inhaled nitric oxide.

A new right ventricular assist device. The extracorporeal pulsatile assist device (EPAD).

Following the discovery of Frostell and colleagues that breathing low concentrations of nitric oxide (NO) produced selective pulmonary vasodilation in awake lambs with experimental pulmonary artery hypertension (PAH), an explosion of laboratory and clinical research led to approval of inhaled NO by the US Food and Drug Administration in 1999, for the treatment of term and near-term neonates with hypoxemia. More than a quarter century later, a large number of studies have demonstrated the efficacy and safety of NO inhalation in a variety of cardiovascular diseases in pediatric and adult patients including chronic PAH and ischemia-reperfusion injury. It is presently estimated that a half-million patients in the United States of America have breathed therapeutic levels of inhaled NO. Results of a recent clinical trial suggests a possible role for inhaled NO in treating hemolysis caused by prolonged cardiopulmonary bypass, expanding the future therapeutic use of NO. This review summarizes the pharmacology and physiological effects of breathing NO and describes the current use of NO in clinical practice. In addition, notable recent research developments in inhaled NO therapy and a new and lightweight and portable method to produce safe and pure NO for inhalation therapy economically by electric plasma discharge in air will be discussed.

Warren M. Zapol

Papers

High-Dose Nitric Oxide From Pressurized Cylinders and Nitric Oxide Produced by an Electric Generator From Air.

Effects of inhaled nitric oxide and l-name on intrapulmonary shunting in an ovine lavage ards model

Radical scavengers protect murine lungs from endotoxin-induced hyporesponsiveness to inhaled nitric oxide.

A new right ventricular assist device. The extracorporeal pulsatile assist device (EPAD).

Inhaled Nitric Oxide—Current Practice and Future Potential Uses and Development