Hypoxic Pulmonary Vasoconstriction in Humans:Tale or Myth

Hypoxic Pulmonary vasoconstriction (HPV) describes the physiological adaptive process of lungs to preserves systemic oxygenation. It has clinical implications in the development of pulmonary hypertension which impacts on outcomes of patients undergoing cardiothoracic surgery. This review examines both acute and chronic hypoxic vasoconstriction focusing on the distinct clinical implications and highlights the role of calcium and mitochondria in acute versus the role of reactive oxygen species and Rho GTPases in chronic HPV. Furthermore it identifies gaps of knowledge and need for further research in humans to clearly define this phenomenon and the underlying mechanism

Cytochrome <em>c</em> oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology.

Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial electron transport chain. The purpose of this study was to analyze the function of lung-specific cytochrome c oxidase subunit 4 isoform 2 (COX4i2) in vitro and in COX4i2-knockout mice in vivo. COX was isolated from cow lung and liver as control and functionally analyzed. COX4i2-knockout mice were generated and the effect of the gene knockout was determined, including COX activity, tissue energy levels, noninvasive and invasive lung function, and lung pathology. These studies were complemented by a comprehensive functional screen performed at the German Mouse Clinic (Institute of Experimental Genetics, Neuherberg, Germany). We show that isolated cow lung COX containing COX4i2 is about twice as active (88 and 102% increased activity in the presence of allosteric activator ADP and inhibitor ATP, respectively) as liver COX, which lacks COX4i2. In COX4i2-knockout mice, lung COX activity and cellular ATP levels were significantly reduced (-50 and -29%, respectively). Knockout mice showed decreased airway responsiveness (60% reduced P(enh) and 58% reduced airway resistance upon challenge with 25 and 100 mg methacholine, respectively), and they developed a lung pathology deteriorating with age that included the appearance of Charcot-Leyden crystals. In addition, there was an interesting sex-specific phenotype, in which the knockout females showed reduced lean mass (-12%), reduced total oxygen consumption rate (-8%), improved glucose tolerance, and reduced grip force (-14%) compared to wild-type females. Our data suggest that high activity lung COX is a central determinant of airway function and is required for maximal airway responsiveness and healthy lung function. Since airway constriction requires energy, we propose a model in which reduced tissue ATP levels explain protection from airway hyperresponsiveness, i.e., absence of COX4i2 leads to reduced lung COX activity and ATP levels, which results in impaired airway constriction and thus reduced airway responsiveness; long-term lung pathology develops in the knockout mice due to impairment of energy-costly lung maintenance processes; and therefore, we propose mitochondrial oxidative phosphorylation as a novel target for the treatment of respiratory diseases, such as asthma.-H&uuml;ttemann, M., Lee, I., Gao, X., Pecina, P., Pecinova, A., Liu, J., Aras, S., Sommer, N., Sanderson, T. H., Tost, M., Neff, F., Aguilar-Pimentel, J. A., Becker, L., Naton, B., Rathkolb, B., Rozman, J., Favor, J., Hans, W., Prehn, C., Puk, O., Schrewe, A., Sun, M., H&ouml;fler, H., Adamski, J., Bekeredjian, R., Graw, J., Adler, T., Busch, D. H., Klingenspor, M., Klopstock, T., Ollert, M., Wolf, E., Fuchs, H., Gailus-Durner, V., Hrabě de Angelis, M., Weissmann, N., Doan, J. W., Bassett, D. J. P., Grossman, L. I. Cytochrome c oxidase subunit 4 isoform 2-knockout mice show reduced enzyme activity, airway hyporeactivity, and lung pathology

Modern and ancient amalgamated sandy meander‐belt deposits: recognition and controls on development

Amalgamated sandy meander belts and their deposits are common in modern continental and marine‐connected basins yet comprise a minor constituent of the reported fluvial rock record. This suggests that either amalgamated meander‐belts are uncommon in the rock record or that the recognition criteria are lacking to identify sandy meandering river deposits. To address this apparent discrepancy, the authors document the range and occurrence of amalgamated sandy meander belts (ASMB) from modern basins and the stratigraphic record. ASMB are widely distributed throughout both present and rock record sedimentary basins occurring in foreland, extensional, cratonic, strike‐slip and passive margin basins. They occur in all climatic settings ranging from tundra to hot deserts. Three specific occurrences of ASMB are recognised in modern basins: in the proximal to medial parts of distributive fluvial systems (DFS), as laterally‐confined belts that mainly form axial fluvial systems; and as valley‐confined meander belts that may infill bedrock, alluvial or coastal plain valleys. From the limited amount of rock record examples of ASMB that are available, it is clear that they occur in similar settings to those observed in modern basins, the recognition of which provides a framework for the further prediction and identification of ASMB in the rock record. The lack of recognition of ASMB in the rock record is considered to be due to an absence of characteristics that allow clear distinction between sandy meandering and braided fluvial deposits. Characteristics considered common to both include: multi‐storey, laterally extensive (sheet‐like) amalgamated channel belts, dominance of downstream accreting bedforms, no fining upwards grain‐size profile and little or no fine‐grained sediment and/or soil preservation. In contrast, features considered characteristic of meandering rivers such as inclined heterolithic stratification, high palaeocurrent dispersion, single storey channels and fining upwards grain‐size profiles are absent. The authors suggest that no single criterion can be used to definitively identify sandy meander belt deposits in the rock record and that a combination of systematic variations in accretion direction, palaeocurrent dispersal patterns and recognition of storey scale accretion surfaces is necessary to identify clearly this fluvial style. The common occurrence and distribution of sandy meander belts in modern sedimentary basins together with their limited recognition in the rock record suggests that their true stratigraphic distribution has yet to be determined. This has important implications for palaeogeographic reconstructions, understanding the impact of plant colonisation on fluvial planform style and predicting sandstone body dimensions and internal heterogeneity distribution within hydrocarbon reservoirs and aquifers