Oxidants, antioxidants, and respiratory tract lining fluids.

Respiratory tract lining fluids (RTLFs) are a heterogeneous group of substances covering the respiratory tract epithelial cells (RTECs) from nasal mucosa to alveoli. Antioxidant contained in the RTLFs can be expected to provide an initial defense against inhaled environmental toxins. The major antioxidants in RTLF include mucin, uric acid, protein (largely albumin), ascorbic acid, and reduced glutathione (GSH). RTLF antioxidants can be augmented by such processes as transudation/exudation of plasma constituents; RTEC secretory processes, including glandular mucus secretion; and cellular antioxidants derived from lysis of RTECs and of inflammatory cells. The antioxidant composition of RTLFs and their role in modulating normal and pathophysiologic RTEC functions under conditions of oxidative stress are yet to be fully characterized

Back-diffusion of CO2 and its influence on the intramural pH in gastric mucosa

We have examined the back-diffusion of CO2 generated by buffering HCl with NaHCO3 in the stomach, observed its influence on the pH in the wall of the gastric mucosa, and compared its effects with those of HCl. Isolated stomachs of 17 anesthetized dogs were exposed to either (1) 250 ml NaCl at pH 7, or (2) 125 ml HCl (12.5 meq) + 125 ml NaHCO3 (12.5 meq) to generate 12.5 meq CO2 in the stomach, or (3) 250 ml HCl alone to give either 12.5 or 35 meq HCl in the stomach. Samples of gastric fluid and arterial blood were collected every 20 min for 6 hr and analyzed for pH and pCO2. The intramural pH of the gastric wall was measured by hollow viscus tonometry. The pCO2 in gastric juice rose to 1184 +/- 139 mm Hg upon the generation of CO2 in the stomach. The t1/2 of the CO2 generated by the buffering of acid was 32 +/- 4 min and of the pCO2 was 18.7 +/- 0.7 min. The t1/2 of an equimolar amount of HCl was 2 hr 42 min +/- 40 min. The disappearance of the CO2 was accompanied by a rise in intragastric pH from 6.0 +/- 0.01 to 6.8 +/- 0.09 (P P < 0.001). In contrast the pH in gastric fluid did not change and the pH in the intramural fluid did not fall below control values following the administration of 12.5 or 35 meq HCl alone.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23929/1/0000175.pd

A study on the safety and efficacy of reveglucosidase alfa in patients with late-onset Pompe disease

Abstract Background Late-onset Pompe disease is a rare genetic neuromuscular disorder caused by lysosomal acid alpha-glucosidase (GAA) deficiency that ultimately results in mobility loss and respiratory failure. Current enzyme replacement therapy with recombinant human (rh)GAA has demonstrated efficacy in subjects with late-onset Pompe disease. However, long-term effects of rhGAA on pulmonary function have not been observed, likely related to inefficient delivery of rhGAA to skeletal muscle lysosomes and associated deficits in the central nervous system. To address this limitation, reveglucosidase alfa, a novel insulin-like growth factor 2 (IGF2)-tagged GAA analogue with improved lysosomal uptake, was developed. This study evaluated the pharmacokinetics, safety, and exploratory efficacy of reveglucosidase alfa in 22 subjects with late-onset Pompe disease who were previously untreated with rhGAA. Results Reveglucosidase alfa plasma concentrations increased linearly with dose, and the elimination half-life was <1.2 h. Eighteen of 22 subjects completed 72 weeks of treatment. The most common adverse events were hypoglycemia (63%), dizziness, fall, headache, and nausea (55% for each). Serious adverse events included hypersensitivity (n = 1), symptomatic hypoglycemia (n = 2), presyncope (n = 1), and acute cardiac failure (n = 1). In the dose-escalation study, all treated subjects tested positive for anti-reveglucosidase alfa, anti-rhGAA, anti-IGF1, and anti-IGF2 antibodies at least once. Subjects receiving 20 mg/kg of reveglucosidase alfa demonstrated increases in predicted maximum inspiratory pressure (13.9%), predicted maximum expiratory pressure (8.0%), forced vital capacity (−0.4%), maximum voluntary ventilation (7.4 L/min), and mean absolute walking distance (22.3 m on the 6-min walk test) at 72 weeks. Conclusions Additional studies are needed to further assess the safety and efficacy of this approach. Improvements in respiratory muscle strength, lung function, and walking endurance in subjects with LOPD may make up for the risk of hypersensitivity reactions and hypoglycemia. Reveglucosidase alfa may provide a new treatment option for patients with late-onset Pompe disease. Trial registration ISRCTN01435772 and ISRCTN01230801 , registered 27 October 2011

Tonometers: Effect of Breathing Enriched 02 Mixtures *

The concentrations of 02 and CO2 in tissues (i.e., the extracellular tissue spaces) can be an index to the relationship between the blood flow and metabolism of an organ. Since the optimal performance of an organ is expected to occur between definable limits of the tissue 02 and CO2 tensions (1, 2), correct values for these gas tensions delineate the most suitable relationship between flow and metabolism during various physiological circumstances. Numerous methods have been devised to measure respiratory gases in tissues, but each is hampered by artifacts that are likely to alter the gas tensions: polarographic needle electrodes implanted in tissues often rupture capillaries or compress blood vessels (3); subcutaneous gas depots are usually associated with extensive pathological changes in contiguous tissues (4, 5); and even a method equating the gas tensions of lymph to those of interstitial fluid results in variable values (6, 7). With these difficulties, it has, for practical purposes, been assumed that the respiratory gas tensions of the draining venous blood are reasonable estimates of the tissue gas tensions; however, comparisons of values for tissue and venous blood gas tensions in a single organ in order to validate this assumption have not been performed. The present study investigates the hollow viscus as a convenient in vivo tonometer in which to equilibrate liquids until they assume the gas tensions of the surrounding tissues. We found that such organs as the urinary bladder act as very rapid and convenient tissue tonomneters and that it is * Submitted for publication August 5, 1963; accepte

Role of the Mast Cell in the Pulmonary Pressor Response to Hypoxia

This study investigated the role of the mast cell in the pulmonary arterial pressor response to hypoxia. We found that pulmonary arteries 50-500 μ in diameter have a predictable distribution of perivascular mast cells; that such pulmonary mast cells are degranulated in vivo during alveolar hypoxia; that hypoxia releases histamine from mast cells isolated from the peritoneal cavity without apparent injury to the cells; and that histamine is released from the lung of intact guinea pigs during alveolar hypoxia, with the rise in pulmonary vascular resistance during this period proportional to the amount of histamine released. These data point to the perivascular pulmonary mast cell in the rat and guinea pig as an important structure in the mediation of the pulmonary pressor response to hypoxia, even though the responsible humoral vasoconstrictor released from such a cell may not be histamine, or histamine alone