Hypercapnia Alters Expression of Immune Response, Nucleosome Assembly and Lipid Metabolism Genes in Differentiated Human Bronchial Epithelial Cells

Abstract

Hypercapnia, the elevation of CO2 in blood and tissues, commonly occurs in severe acute and chronic respiratory diseases, and is associated with increased risk of mortality. Recent studies have shown that hypercapnia adversely affects innate immunity, host defense, lung edema clearance and cell proliferation. Airway epithelial dysfunction is a feature of advanced lung disease, but the effect of hypercapnia on airway epithelium is unknown. Thus, in the current study we examined the effect of normoxic hypercapnia (20% CO2 for 24 h) vs normocapnia (5% CO2), on global gene expression in differentiated normal human airway epithelial cells. Gene expression was assessed on Affymetrix microarrays, and subjected to gene ontology analysis for biological process and cluster-network representation. We found that hypercapnia downregulated the expression of 183 genes and upregulated 126. Among these, major gene clusters linked to immune responses and nucleosome assembly were largely downregulated, while lipid metabolism genes were largely upregulated. The overwhelming majority of these genes were not previously known to be regulated by CO2. These changes in gene expression indicate the potential for hypercapnia to impact bronchial epithelial cell function in ways that may contribute to poor clinical outcomes in patients with severe acute or advanced chronic lung diseases.

Elevated CO2 regulates the Wnt signaling pathway in mammals, Drosophila melanogaster and Caenorhabditis elegans

“…Although initially thought to be benign or even protective 5,6 , it is becoming increasingly evident that hypercapnia has significant pathophysiological effects that may be deleterious to organs such as the lung 7–10 and skeletal muscles 11 . Recent discoveries suggest that elevation of CO 2 activates specific signal transduction pathways with adverse consequences for cellular and organismal functions not only in mammals 7,9,12–14 , but also fish 15 , fly Drosophila melanogaster 16,17 , and nematode Caenorhabditis elegans 17,18 . Hypercapnia has also been reported to alter gene expression in different tissues, cells and species 7,12,16,18,19 .…”

Hypercapnia: An Aggravating Factor in Asthma

“…In adult flies and the Drosophila S2 cell line, hypercapnia suppressed induction of genes involved in specific antimicrobial peptides such as diptericin that are regulated by Relish, an orthologue of the mammalian transcription factor NF-κB [ 111 ]. Transcriptomic studies in mouse neonatal lung tissue and human bronchial epithelial cells reported that hypercapnia altered the expression of components of the innate immune system [ 38 , 39 ]. It downregulated the expression of inflammatory mediator genes including interferons, interleukins, chemokines and tumor necrosis factor (TNF) in the neonatal lung [ 38 ].…”

“…It downregulated the expression of inflammatory mediator genes including interferons, interleukins, chemokines and tumor necrosis factor (TNF) in the neonatal lung [ 38 ]. In human bronchial epithelial cells, hypercapnic respiratory acidosis resulted in downregulation of genes related to the interleukin 6 (IL-6) receptor and chemokines [ 39 ]. Hypercapnia selectively inhibited the expression of IL-6 and TNF, and decreased phagocytosis in human and mouse alveolar macrophages [ 33 ].…”

“…However, in recent years, it has become increasingly evident that elevated CO 2 acts as a gaso-signaling molecule, resulting in deleterious effects in various organs such as the lung [ 23 , 24 , 25 , 26 , 27 , 28 , 29 ] and skeletal muscles [ 30 , 31 , 32 ] as well as innate immunity system [ 25 , 29 , 33 , 34 , 35 , 36 , 37 ]. In the lung, recent studies reported that high levels of CO 2 activate specific gene expression [ 26 , 38 , 39 , 40 ] and signal transduction pathways with adverse consequences on alveolar fluid clearance through Na, K-ATPase endocytosis via intracellular calcium- or extracellular signal-regulated kinase (ERK)-mediated AMP-activated protein kinase (AMPK)/protein kinase C-ζ/c-Jun-N-Terminal Kinase (JNK) signaling or soluble adenylyl cyclase-mediated protein kinase A-Iα signaling [ 24 , 41 , 42 , 43 , 44 , 45 , 46 ] and epithelial cell repair via AMPK-mediated Rac1-GTPase signaling, NF-κB pathways or miR-183-regulated mitochondrial dysfunction [ 28 , 47 , 48 , 49 ]. In addition, a secondary analysis of three prospective non-interventional cohort studies of ARDS patients receiving mechanically ventilation reported that severe hypercapnia was independently associated with higher ICU mortality [ 23 ].…”

Mechanism of benefit of non‐invasive ventilation in COPD with hypercapnic respiratory failure

“…Recent studies from our laboratory suggest another previously unappreciated mechanism that may underlie the benefits of reducing hypercapnia by the application of NIV. We have shown that elevated levels of CO 2 selectively decrease expression of innate immune and antiviral genes in myeloid 2 and lung epithelial cells, 3 and that hypercapnia increases the mortality of bacterial pneumonia 4 and influenza A infection 5 in mice. These effects are pH-independent and mediated by specific intracellular signalling events triggered by high concentrations of molecular CO 2 .…”