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      Metabolic Functions of the Lung, Disorders and Associated Pathologies

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          Abstract

          The primary function of the lungs is gas exchange. Approximately 400 million years ago, the Earth’s atmosphere gained enough oxygen in the gas phase for the animals that emerged from the sea to breathe air. The first lungs were merely primitive air sacs with a few vessels in the walls that served as accessory organs of gas exchange to supplement the gills. Eons later, as animals grew accustomed to a solely terrestrial life, the lungs became highly compartmentalized to provide the vast air-blood surface necessary for O 2 uptake and CO 2 elimination, and a respiratory control system was developed to regulate breathing in accordance with metabolic demands and other needs. With the evolution and phylogenetic development, lungs were taking a variety of other specialized functions to maintain homeostasis, which we will call the non-respiratory functions of the lung and that often, and by mistake, are believed to have little or no connection with the replacement gas. In this review, we focus on the metabolic functions of the lung, perhaps the least known, and mainly, in the lipid metabolism and blood-adult lung vascular endothelium interaction. When these functions are altered, respiratory disorders or diseases appear, which are discussed concisely, emphasizing how they impact the most important function of the lungs: external respiration.

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          Most cited references169

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          Immunology of asthma and chronic obstructive pulmonary disease.

          Asthma and chronic obstructive pulmonary disease (COPD) are both obstructive airway diseases that involve chronic inflammation of the respiratory tract, but the type of inflammation is markedly different between these diseases, with different patterns of inflammatory cells and mediators being involved. As described in this Review, these inflammatory profiles are largely determined by the involvement of different immune cells, which orchestrate the recruitment and activation of inflammatory cells that drive the distinct patterns of structural changes in these diseases. However, it is now becoming clear that the distinction between these diseases becomes blurred in patients with severe asthma, in asthmatic subjects who smoke and during acute exacerbations. This has important implications for the development of new therapies.
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            Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1.

            Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding angiogenic growth factors, which are secreted by hypoxic cells and stimulate endothelial cells, leading to angiogenesis. To determine whether HIF-1 also mediates cell-autonomous responses to hypoxia, we have compared gene expression profiles in arterial endothelial cells cultured under nonhypoxic versus hypoxic conditions and in nonhypoxic cells infected with adenovirus encoding beta-galactosidase versus a constitutively active form of HIF-1alpha (AdCA5). There were 245 gene probes that showed at least 1.5-fold increase in expression in response to hypoxia and in response to AdCA5; 325 gene probes showed at least 1.5-fold decrease in expression in response to hypoxia and in response to AdCA5. The largest category of genes down-regulated by both hypoxia and AdCA5 encoded proteins involved in cell growth/proliferation. Many genes up-regulated by both hypoxia and AdCA5 encoded cytokines/growth factors, receptors, and other signaling proteins. Transcription factors accounted for the largest group of HIF-1-regulated genes, indicating that HIF-1 controls a network of transcriptional responses to hypoxia in endothelial cells. Infection of endothelial cells with AdCA5 under nonhypoxic conditions was sufficient to induce increased basement membrane invasion and tube formation similar to the responses induced by hypoxia, indicating that HIF-1 mediates cell-autonomous activation of endothelial cells.
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              Genome-wide Association of Hypoxia-inducible Factor (HIF)-1α and HIF-2α DNA Binding with Expression Profiling of Hypoxia-inducible Transcripts*

              Hypoxia-inducible factor (HIF) controls an extensive range of adaptive responses to hypoxia. To better understand this transcriptional cascade we performed genome-wide chromatin immunoprecipitation using antibodies to two major HIF-α subunits, and correlated the results with genome-wide transcript profiling. Within a tiled promoter array we identified 546 and 143 sequences that bound, respectively, to HIF-1α or HIF-2α at high stringency. Analysis of these sequences confirmed an identical core binding motif for HIF-1α and HIF-2α (RCGTG) but demonstrated that binding to this motif was highly selective, with binding enriched at distinct regions both upstream and downstream of the transcriptional start. Comparison of HIF-promoter binding data with bidirectional HIF-dependent changes in transcript expression indicated that whereas a substantial proportion of positive responses (>20% across all significantly regulated genes) are direct, HIF-dependent gene suppression is almost entirely indirect. Comparison of HIF-1α- versus HIF-2α-binding sites revealed that whereas some loci bound HIF-1α in isolation, many bound both isoforms with similar affinity. Despite high-affinity binding to multiple promoters, HIF-2α contributed to few, if any, of the transcriptional responses to acute hypoxia at these loci. Given emerging evidence for biologically distinct functions of HIF-1α versus HIF-2α understanding the mechanisms restricting HIF-2α activity will be of interest.
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                Author and article information

                Journal
                J Clin Med Res
                J Clin Med Res
                Elmer Press
                Journal of Clinical Medicine Research
                Elmer Press
                1918-3003
                1918-3011
                October 2016
                30 August 2016
                : 8
                : 10
                : 689-700
                Affiliations
                [a ]Internal Medicine and Neumology, Clinica de Diagnostico Medico, San Jose, Costa Rica
                [b ]Medicine and General Surgery, Medicine School, University of Costa Rica, San Jose, Costa Rica
                Author notes
                [c ]Corresponding Author: Alcibey Alvarado, Clinica de Diagnostico Medico, Torre Medica, 3 piso, Paseo, Colon, San Jose, Costa Rica. Email: alcialvagonza@ 123456yahoo.com.mx
                Article
                10.14740/jocmr2668w
                5012236
                27635172
                fa96cf11-10e9-44c0-b7ac-d540e01534a9
                Copyright 2016, Alvarado et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 08 August 2016
                Categories
                Review

                Medicine
                metabolic functions,lung,lipid and pulmonary surfactant,blood-endothelial interactions

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