Sickle cell disease

A radical is any molecule that contains one or more unpaired electrons. Radicals are normally generated in many metabolic pathways. Some of these radicals can exist in a free form and subsequently interact with various tissue components resulting in dysfunction. The potential role of oxygen- or xenobiotic-derived free radicals in the pathology of several human diseases has stimulated extensive research linking the toxicity of numerous xenobiotics and disease processes to a free radical mechanism. However, because free radical-mediated changes are pervasive and often poorly understood, the question of whether such species are a major cause of tissue injury and human disease remains equivocal. This review discusses cellular sources of various radical species and their reactions with vital cellular constituents. Examples of purported free radical-mediated disorders are discussed in detail to provide insights into the controversy over whether free radicals are important mediators of tissue injury.

Free radicals as mediators of tissue injury and disease.

The causes of acute rhabdomyolysis include trauma, drugs, toxins, and certain infections. Acute kidney injury is a dangerous complication of severe rhabdomyolysis. This review summarizes current views on the pathogenesis of myoglobin-induced kidney injury as well as on its prevention and treatment.

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Rhabdomyolysis and Acute Kidney Injury

Reperfusion injury, the paradoxical tissue response that is manifested by blood flow-deprived and oxygen-starved organs following the restoration of blood flow and tissue oxygenation, has been a focus of basic and clinical research for over 4-decades. While a variety of molecular mechanisms have been proposed to explain this phenomenon, excess production of reactive oxygen species (ROS) continues to receive much attention as a critical factor in the genesis of reperfusion injury. As a consequence, considerable effort has been devoted to identifying the dominant cellular and enzymatic sources of excess ROS production following ischemia-reperfusion (I/R). Of the potential ROS sources described to date, xanthine oxidase, NADPH oxidase (Nox), mitochondria, and uncoupled nitric oxide synthase have gained a status as the most likely contributors to reperfusion-induced oxidative stress and represent priority targets for therapeutic intervention against reperfusion-induced organ dysfunction and tissue damage. Although all four enzymatic sources are present in most tissues and are likely to play some role in reperfusion injury, priority and emphasis has been given to specific ROS sources that are enriched in certain tissues, such as xanthine oxidase in the gastrointestinal tract and mitochondria in the metabolically active heart and brain. The possibility that multiple ROS sources contribute to reperfusion injury in most tissues is supported by evidence demonstrating that redox-signaling enables ROS produced by one enzymatic source (e.g., Nox) to activate and enhance ROS production by a second source (e.g., mitochondria). This review provides a synopsis of the evidence implicating ROS in reperfusion injury, the clinical implications of this phenomenon, and summarizes current understanding of the four most frequently invoked enzymatic sources of ROS production in post-ischemic tissue.

Reperfusion injury and reactive oxygen species: The evolution of a concept.

Pulmonary strategies of antioxidant defense.

The other medical causes of rhabdomyolysis.

The effect of ischemia reperfusion or hypoxia reoxygenation on pulmonary vascular permeability and resistance was studied in 25 isolated blood-perfused dog lungs. Vascular permeability, assessed by determining filtration coefficient (Kf), and vascular resistances were measured at the beginning and end of the experiment. Ischemia reperfusion was produced by occluding blood flow to the lung for 3 h and reperfusing for 1 h, whereas hypoxia reoxygenation was obtained by ventilating the lung with 95% N2-5% CO2 for 3 h and then ventilating with 95% O2-5% CO2 for 1 h with no interruption of perfusion. There was a significant increase in Kf in both ischemia reperfusion and hypoxia reoxygenation groups (51 and 85%, respectively), and total vascular resistance increased greatly in both groups (386 and 532%, respectively). Two additional groups were also studied in which the ischemia reperfusion or hypoxia reoxygenation lungs were pretreated with allopurinol (20 micrograms/ml). The Kf did not significantly increase in either the allopurinol ischemia reperfusion or the allopurinol hypoxia reoxygenation groups (22 and 6%, respectively). However, total vascular resistance significantly increased in both groups (239 and 224%, respectively). Although vascular permeability is modestly increased by both ischemia reperfusion and hypoxia reoxygenation, the predominant change in these conditions is the increased vascular resistance, which predominantly affects the postcapillary resistance and would result in a greater tendency for edema to develop in these slightly damaged lungs. Allopurinol, which inhibits xanthine oxidase, attenuated the permeability changes in both groups and may be useful in preventing ischemia reperfusion injury in certain conditions.

Effect of ischemia reperfusion or hypoxia reoxygenation on lung vascular permeability and resistance.

Pulmonary artery catheters are frequently used to measure pulmonary vascular pressures, particularly the pulmonary wedge pressure (Pw), which reflects pulmonary venous and ideally left atrial pressures. However, the pulmonary capillary pressure (Pc) is the major force in the formation of pulmonary edema. Unfortunately, Pw has been interpreted as being identical to Pc. In this study we used 7-Fr pulmonary artery catheters to measure effective Pc in closed-chest animals and patients. The decreasing pressure profile after pulmonary artery occlusion was separated into fast and slow components, with the inflection point between them representing Pc. Pc was also estimated by mathematically analyzing the curves in terms of a precapillary resistance, a large pulmonary capillary capacitor, and a postcapillary resistance. In dogs, Pc was determined after pulmonary vascular resistance had been increased by infusing serotonin and histamine. While Pw remained unchanged, serotonin increased pulmonary artery pressure (Ppa) 52% and Pc 16%, whereas histamine increased Ppa only 25%, but increased Pc by 35%. This is consistent with studies showing that serotonin primarily elevates precapillary resistance, and histamine increases postcapillary resistance. In thoracic surgery patients, Pc was not consistently related to Pw. This measurement was simple, reproducible, and provided a more precise capillary filtration pressure than Pw. It should be clinically useful in monitoring patients with pulmonary hypertension and adult respiratory distress syndrome, especially those with pulmonary artery catheters.

Measurement of effective pulmonary capillary pressure using the pressure profile after pulmonary artery occlusion.

The extravascular thermal volume of the lung (ETV) has been measured in dogs as the difference between mean transit time (t) volumes for heat and indocyanine green dye across the pulmonary circulation, calculated as the product of thermal dilution cardiac output (CO) and the difference in t for aortic indicator-dilution curves generated by right and left atrial injections. ETV measurements were compared with the extravascular lung mass (ELM): in 21 normal dogs, ETV/ELM = 1.11 +/- 0.14 (SD); in 17 dogs with hydrostatic pulmonary edema (up to 21 g/kg), ETV/ELM = 0.90 +/- 0.11; and in 27 dogs with alloxan pulmonary edema (up to 51 g/kg); ETV/ELM = 0.93 +/- 0.13. For all 65 dogs the mean ETVELM was 0.98 +/- 0.15, and the liner regression was ETV (ml/kg) = 0.90 ELM (g/kg) + 0.86 +/- 2.25 (SEE; r = 0.96). Calculations based on measurements of lung specific heat predict that ETV/ELM should equal 0.984. With acute changes in pulmonary hemodynamics, ETV was reduced by reductions in pulmonary arterial pressure (Ppa) sufficient to produce zone 1 conditions at the top of the lung. However, ETV was not affected by increases in CO (mean = 50%) produced by nitroprusside or by increases in Ppa and pulmonary blood volume (mean = 27%) produced by partial mitral valve obstruction. Distortion of the thermal dilution curve due to position of the arterial thermistor appears to be the greatest source of variability and overestimation. Simultaneous measurements from pairs of thermistors differed by 14% (range 0.4–50%).

Effect of edema and hemodynamic changes on extravascular thermal volume of the lung

https://www.amjmed.com/article/0002-9343(86)90624-8/pdf

Ronald C. Allison

Papers

The other medical causes of rhabdomyolysis.

Effect of ischemia reperfusion or hypoxia reoxygenation on lung vascular permeability and resistance.

Measurement of effective pulmonary capillary pressure using the pressure profile after pulmonary artery occlusion.

Effect of edema and hemodynamic changes on extravascular thermal volume of the lung

Pulmonary edema: Complication in the management of sickle cell pain crisis