Li, Chuanyu, and Robert M. Jackson. Reactive species mechanisms of cellular hypoxia-reoxygenation injury. Am J Physiol Cell Physiol 282: C227-C241, 2002; 10.1152/ajpcell.00112.2001.-Exacerbation of hypoxic injury after restoration of oxygenation (reoxygenation) is an important mechanism of cellular injury in transplantation and in myocardial, hepatic, intestinal, cerebral, renal, and other ischemic syndromes. Cellular hypoxia and reoxygenation are two essential elements of ischemia-reperfusion injury. Activated neutrophils contribute to vascular reperfusion injury, yet posthypoxic cellular injury occurs in the absence of inflammatory cells through mechanisms involving reactive oxygen (ROS) or nitrogen species (RNS). Xanthine oxidase (XO) produces ROS in some reoxygenated cells, but other intracellular sources of ROS are abundant, and XO is not required for reoxygenation injury. Hypoxic or reoxygenated mitochondria may produce excess superoxide (O 2 Ϫ ) and release H2O2, a diffusible long-lived oxidant that can activate signaling pathways or react vicinally with proteins and lipid membranes. This review focuses on the specific roles of ROS and RNS in the cellular response to hypoxia and subsequent cytolytic injury during reoxygenation.anoxia; ischemia; reperfusion BACKGROUND

It is unclear what role the experimental drug and convalescent plasma had in the recovery of these patients. Prospective clinical trials are needed to delineate the role of investigational therapies in the care of patients with EVD.

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INTRODUCTION: Pulmonary rehabilitation is effective for patients with COPD, but its benefit is less clearly established in idiopathic pulmonary fibrosis (IPF), especially in regard to levels of physical activity and health-related quality of life. The objectives were to determine whether pulmonary rehabilitation increased physical activity as assessed by the International Physical Activity Questionnaire (IPAQ), and improved quality of life and symptoms as assessed by the St George respiratory questionnaire for IPF (SGRQ-I) and the Borg dyspnea index (BDI). METHODS: Subjects who met current criteria for IPF were randomized to a 3-month pulmonary rehabilitation program (n ‫؍‬ 11) or to a control group (n ‫؍‬ 10). The rehabilitation group participated in twiceweekly, 90-min exercise sessions (24 total sessions). The control group maintained its preceding, normal physical activity. All subjects underwent 6-min walk tests to assess the postexertion BDI. The SGRQ-I and a 5-point self-assessment of health were completed at baseline, after 3 months of intervention or observation, and after 3-month follow-up. All subjects completed the IPAQ weekly. RESULTS: Subjects in the rehabilitation group maintained significantly higher levels of physical activity throughout the 3-month rehabilitation program (rehabilitation: 51,364 ؎ 57,713 [mean ؎ SD] metabolic equivalent of task-minutes; control: 20,832 ؎ 37,155, P ‫؍‬ .027 by 2-tailed Mann-Whitney test). SGRQ-I symptom domain scores improved considerably by ؊9 ؎ 22 in the rehabilitation group, whereas in the control group they worsened (16 ؎ 12 rehabilitation compared with control, P ‫؍‬ .013 by 2-tailed Mann-Whitney test). During the 3-month follow-up, self-reported physical activity levels in the rehabilitation group were 14,428 ؎ 8,884 metabolic equivalent of task-minutes and in the control group 16,923 ؎ 32,620 (P ‫؍‬ .17 by 2-tailed Mann-Whitney test), demonstrating substantial reversal of activity in the rehabilitation group. BDI scores after 6-min walk tests did not change significantly. CONCLUSIONS: A 3-month rehabilitation program significantly improved symptoms (SGRQ-I) and physical activity levels (IPAQ) in subjects with IPF while they participated actively in the program. (ClinicalTrials.gov registration NCT01118221.) Key words: idiopathic pulmonary fibrosis; pulmonary rehabilitation; exercise; quality of life.

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The recent immunopurification and cloning of various lung Na+ channel proteins has provided the necessary tools to study Na+ transport at a fundamental level across a number of epithelial tissues. Various macroscopic measurements of Na+ transport have shown that Na+ ions enter the cytoplasm of alveolar cells mainly through amiloride-inhibitable Na+ channels. Molecular biology studies have shown the existence of three Na+ channel subunit mRNAs (alpha-, beta-, and gamma-rENaC) in mature fetal (FDLE) and adult alveolar type II (ATII) cells. Patch-clamp studies have demonstrated the existence of various types of amiloride-inhibitable Na+ channels, located in the apical membranes of FDLE and ATII cells. beta-Agonists and agents that enhance intracellular adenosine 3',5'-cyclic monophosphate levels increase the open probability of these channels, leading to increased Na+ transport across the alveolar epithelium in vivo. Immunopurification of a putative channel protein from adult ATII cells showed that it contains an amiloride-binding subunit with a molecular mass of 150 kDa. When this protein was reconstituted in planar lipid bilayers, it exhibited single channels with a conductance of 25 pS, which were moderately selective for Na+ over K+. The open probability of these channels was increased by the addition of protein kinase A (PKA) and ATP, and was decreased to the same extent by addition of [N-ethyl-N-isopropyl]-2'-4'-amiloride (EIPA) and amiloride (1 microM each) in the apical side of the bilayer, in agreement with the results of patch-clamp studies in ATII cells. Exposure of rats to sublethal hyperoxia increased alpha-rENaC mRNA and the functional expression of Na+ channels in alveolar epithelial cells and limited alveolar edema. These findings indicate that alveolar epithelial channels contain at least one family of amiloride-sensitive Na+ channel proteins, which displays a number of unique properties, including sensitivity to EIPA.

Pulmonary rehabilitation effectively maintained exercise oxygen uptake over 3 months and lengthened constant load exercise time in patients with moderately severe IPF. Exercise endurance on cycle ergometry testing was limited by dyspnea and severe hypoxemia associated with systemic oxidant stress.

We investigated the cellular and molecular events associated with the increase in sodium transport across the alveolar epithelium of rats exposed to hyperoxia (85% 02 for 7 days followed by 100O 02 for 4 days). Alveolar type II (ATII) cell RNA was isolated and probed with a cDNA for one of the rat colonic epithelial sodium channel subunits (arENaC). The arENaC mRNA (3.7-kb transcript) increased 3-fold in ATII cell RNA isolated from rats exposed to 85% 02 for 7 days and 6-fold after 4 days of subsequent exposure to 100% 02. In situ hybridization revealed increased expression of arENaC mRNA transcripts in both airway and alveolar epithelial cells of hyperoxic rats. When immunostained with a polyclonal antibody to kidney sodium channel protein, ATH cells from hyperoxic rats exhibited a significant increase in the amount of immunogenic protein present in both the plasma membrane and the cytoplasm. When patched in the whole-cell mode, ATII cells from hyperoxic rats exhibited amiloride and 5-(N-ethyl-N-isopropyl)-2',4'-amiloride (EIPA)-sensitive currents that were 100%o higher compared with those obtained from air-breathing rats. Single-channel sodium currents (mean conductance of 25 pS) were seen in ATII cells patched in both the inside-out and cell-attached modes. The number and open probability of these channels increased significantly during exposure to hyperoxia. Exposure to sublethal hyperoxia up-regulated both arENaC mRNA and the functional expression of sodium channels in ATII cells.Reabsorption of fluid by alveolar epithelial cells keeps alveoli dry and ensures normal gas exchange. Sodium ion(s) (Na+) enter the apical membranes of alveolar epithelial type II (ATII) cells mainly through amiloride-sensitive ion channels and are actively transported across the basolateral membranes of these cells by the ouabain-sensitive Na+/K+-ATPase (1).Alveolar fluid is reabsorbed across the epithelium by the resulting osmotic gradient.Diverse pathological conditions, including prolonged inhalation of oxidant gases, have been associated with increased production of reactive oxygen and nitrogen species and extensive injury to the alveolar epithelium, resulting in increased protein permeability, pulmonary edema, and compromised gas exchange (2, 3). Survival during oxidant stress depends on the magnitude of the oxidant load and the ability of the animals to mount appropriate defenses. Rats exposed to 85% 02 for 7 days survive a subsequent exposure to 100% 02 for 4 days (4)-an exposure that is lethal to normal rats. Tolerance to hyperoxia was assumed to be the result of induction of antioxidant enzymes. The demonstrated increase of Na+ transport across the alveolar epithelium of both rats and humans exposed to sublethal oxidant stress may also play a vital role in resolving pulmonary edema and thus limiting arterial hypoxemia (5-8). Since the majority of resistance to transcellular movement of Na+ is encountered across the apical membranes and a large fraction of this transport occurs through amiloridesensitive ion channe...