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Characterization of Hypercapnia Effects in Experimental Models with or without Acute Lung Injury: A Scoping Review

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28 August 2024

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Abstract
Background: Ventilatory strategies in acute respiratory distress syndrome patients aim to mitigate the risk of acute lung injury (ALI). However, prolonged utilization of these strategies may precipitate alveolar carbon dioxide elevation and pH reduction. This scoping review endeavors to present extant knowledge concerning hypercapnia effects in experimental models, with or without ALI, specifically focusing on delineating the immunologically mediated pulmonary tissue damage; Methods: A systematic exploration encompassing PubMed, Web of Science, ScienceDirect, Cochrane Reviews, and Scielo databases was undertaken. Articles published between January 1, 2008, and December 31, 2022, were screened for their elucidation of hypercapnia's immunological impact on lung tissue, utilizing experimental or biological models, irrespective of ALI presence; Results: Following duplicate removal and predefined criteria filtering, 30 pertinent articles scrutinizing hypercapnia's influence on pulmonary epithelium were identified. It was observed that hypercapnia induces perturbations in innate immune response gene transcription, mediated via Nuclear Factor-kappa B attenuation. Furthermore, a compromised innate immune response against injurious agents was noted. Concurrently, disruption and subsequent resealing of alveolar epithelial cells were evidenced, primarily through Na/K-ATPase endocytosis, impeding fluid reabsorption at the alveolar epithelium level; Conclusions: In experimental settings, with or without ALI, hypercapnia's immunomediated mechanisms exacerbate innate immune system impairment and disrupt the respiratory epithelium's repair and healing processes.
Keywords: 
Subject: Medicine and Pharmacology  -   Pulmonary and Respiratory Medicine

1. Introduction

Acute Lung Injury (ALI), clinically exemplified as Acute Respiratory Distress Syndrome (ARDS), stands as a condition causing substantial mortality annually, while also imposing a considerable financial burden on healthcare resources [1,2,3]. The implementation of "protective" ventilatory strategies for ARDS mitigation has been instrumental in reducing the incidence of Ventilator-Induced Lung Injury (VILI), mitigating organ failure, and curtailing mortality rates [4,5,6]. Nonetheless, these strategies may inadvertently result in alveolar carbon dioxide (CO2) elevation and subsequent pH decline over protracted periods [4,5]. This ancillary consequence has been embraced under the term "permissive hypercapnia," positing it as a beneficial approach in ARDS management, alongside obstructive pathologies, among others [7,8,9]. Recent investigations have underscored the clinical ramifications of hypercapnia, demonstrating its significance as an autonomous predictor of mortality [10,11], along with implying a heightened ARDS severity among patients exhibiting sustained hypercapnia [12,13]. However, current evidence pertaining to hypercapnia's clinical impact remains scant, with contradictory perspectives on its underlying pathophysiological mechanisms [14,15]. Preclinical endeavors have elucidated hypercapnia's impact across various cellular strata within lung tissue [10,12,15,16,17,18,19].
Initial perusal of literature failed to unearth systematic reviews delving into the subject matter. Undertaking a scoping review, therefore, assumes paramount importance, serving to map out available literature and discern its relevance in informing future clinical investigations.
To furnish available insights into hypercapnia's effects within experimental paradigms, both with and without ALI, this scoping review endeavors to pinpoint and delineate the immunologically mediated repercussions of hypercapnia at the pulmonary tissue level. The overarching objective of this scoping review is to present extant literature pertaining to hypercapnia's effects within experimental models, encompassing acute lung injury scenarios, to characterize the immunomediated pulmonary tissue damage. The central inquiry guiding this review is: What are the immunomediated effects of hypercapnia in experimental models, with or without acute lung injury?

2. Results

The electronic database search yielded 3541 records, supplemented by an additional 113 records sourced from alternative channels, resulting in a total of 3654 articles. Following deduplication using Endnote X8, 2371 unique articles remained. Subsequent screening of titles and abstracts led to the exclusion of 2289 articles. Thereafter, a detailed examination of 82 full-text articles was conducted by two research team members to assess their eligibility for inclusion in the scoping review, with an additional 52 articles excluded for failing to address the research question. Ultimately, 30 articles met the inclusion criteria (Figure 1; PRISMA Flow Diagram summarizing the search strategy). Furthermore, details of the experimental articles, including authorship, publication year, and country of origin, are provided in Table 1.
In the subsequent phase of the review, data extraction and synthesis of results from the included studies were conducted in accordance with the study objectives and research question. This extraction process adhered to the scoping review methodology delineated by Levac et al. [20]. Subsequently, these results were categorized based on the effect of hypercapnia on pulmonary tissue, particularly focusing on the respiratory epithelium and the innate immune response, defined as the primary line of defense, encompassing phagocytes (neutrophils and macrophages), dendritic cells, and complement proteins [21].

2.1. Innate Immune Response

Hypercapnia exerts transcriptional alterations within the innate immune response, as reported in 33.3% (n = 10/30) of the included articles [22,18,23,24,25,26,27,28,29,30]. Among the 10 experimental studies, 80% (8/10) indicated that the most prevalent mechanism by which hypercapnia modulates innate immune response transcription is by attenuating the canonical Nuclear Factor-kappa B (NF-kB) pathway [22,23,25,26,27,28]. Another notable effect observed in experimental studies is the compromised capacity of the innate immune response against external aggressors, documented in 50% (n = 15/30) of the reviewed articles [18,23,24,26,17,31,32,33,34,35,36,37], with particular emphasis on 4 in vivo models of ALI attributable to infectious agents, where hypercapnia adversely affected phagocytic activity [18,17,31,33]. Moreover, in one biological model, hypercapnia was found to reduce autophagy and bacterial viability [35]. Additionally, a subset of biological models identified hypercapnia's propensity to dampen the expression of genes associated with the inflammatory response [23,24,26,30,32,33,34,36,37]. Conversely, Gates et al.[33] demonstrated that hypercapnia exacerbated mortality, elevated bacterial load, and decreased pulmonary levels of interleukin 6 (IL-6) and tumor necrosis factor (TNF) during the early stages of infection in an ALI model induced by pneumonia (see Table 2).

2.2. Respiratory epithelium

Hypercapnia-induced disruption and subsequent resealing of alveolar epithelial cells were observed in 36.7% (n = 11/30) of the experimental studies included in the scoping review [22,38,39,40,41,42,43,44,45,46,47,48]. Mechanisms elucidated in these studies include reports of elevated CO2 levels promoting Na/K-ATPase endocytosis, thereby impeding fluid reabsorption at the alveolar epithelium [38,40,42,46,47,48]. Moreover, other investigations highlighted hypercapnia's impact on respiratory epithelium healing and repair [22,39,41,42,43,45]. See Table 2 for details.
Based on these findings, two graphical immunological models depicting the immunomediated effects of hypercapnia are proposed (Figure 2 and Figure 3).

3. Discussion

Authors should discuss the results and how they can be interpreted from the perspective of previous studies and of the working hypotheses. The findings and their implications should be discussed in the broadest context possible. Future research directions may also be highlighted. Our review delineated that in experimental models, with or without lung injury, hypercapnia, irrespective of metabolic acidosis, can influence innate cellular response by attenuating the canonical NF-kB pathway. This pathway serves as a pivotal transcription factor regulating genes associated with immunity, repair, and inflammation, thereby diminishing autophagy, bacterial death, and modulating the inflammatory response by attenuating IL-6 and TNF production [10,22,23,25,26,27,28,49,50,51]. Consequently, a reduced capacity of the innate immune response against aggressor agents ensues, affecting phagocyte activity, autophagy, bacterial death, and the expression of inflammatory molecules, thereby facilitating bacterial propagation and replication [30,31,32,33,34,35,36,37,52,53,54].
As per experimental investigations, the mechanism underlying hypercapnia's alteration of the respiratory epithelium, with or without metabolic acidosis, involves inhibiting fluid reabsorption at the alveolar epithelium level through various pathways. This includes an upsurge in cytosolic Ca++ concentration, initiating a cascade implicating calcium-calmodulin-dependent kinases, which induce AMPc-activated protein kinase expression, thereby promoting endocytosis and reducing Na/K-ATPase transporters on the basal membrane of the alveolar epithelium, ultimately impacting pulmonary clearance [38,40,42,44,46,47,48,55,56,57]. Another reported mechanism in preclinical models indicates that exposure to hypercapnia contributes to deficient respiratory epithelium repair by activating adenylate cyclase, thereby delaying the resealing and repair of alveolar epithelia [22,39,45].

3.1. Study Limitations

The aim of our study was to furnish a comprehensive scoping review encompassing all extant literature concerning the effects of hypercapnia in experimental models, with or without lung injury. Although our search strategy was designed in accordance with PRISMA guidelines, we acknowledge the potential omission of eligible studies from alternative databases. Furthermore, due to the adopted methodology, our review lacked a methodological quality assessment of the included studies. Despite these constraints, our review comprehensively encapsulated all experimental models, potentially guiding future research endeavors aimed at elucidating the immunological implications of hypercapnia and its clinical ramifications in patients with or without lung injury.

4. Materials and Methods

4.1. Eligibility criteria

The methodology employed in this review adheres to the scoping review methodologies delineated by Levac et al. in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses—Extension for Scoping Reviews (PRISMA-ScR) guidelines [20]. The principal aim was to delineate the immunologically mediated effects of hypercapnia on pulmonary tissue (Table A1). Solely studies conducted in experimental models were encompassed, given the absence of clinical investigations. The review exclusively considered data published in English and Spanish between January 1, 2008, and December 31, 2022.

4.2. Search strategy

A tripartite search strategy was enacted. Initially, exploration was confined to PubMed, Web of Science, ScienceDirect, Cochrane Reviews, and Scielo to identify terms and keywords present within titles and abstracts. Subsequently, a comprehensive search encompassing all identified keywords and terms across all enlisted databases was executed. Thirdly, manual perusal of reference lists was conducted to identify articles furnishing supplementary information.

4.3. Information sources

The search was conducted across diverse databases, namely PubMed, Web of Science, ScienceDirect, Cochrane Reviews, and Scielo. To encapsulate preclinical research, search terms encompassed experimental or biological models. The search strategy amalgamated MeSH terms and pertinent keywords, tailored to each database, encompassing acute lung injury, adult respiratory distress syndrome, pneumonia, in tandem with hypercapnia and anti-inflammation. Please refer to Table A2 for the exhaustive search strategy.

4.4. Data Extraction

Relevant data from included studies were methodically extracted to address the review query, in alignment with the methodological framework delineated by Levac et al. [20]. Extracted parameters encompassed the demographic profile of the studied population, experimental or biological models with or without ALI, focal domain, and the immunologically mediated ramifications of hypercapnia on pulmonary tissue. To classify the thematic underpinning of the research, precedence was accorded to antecedent investigations, which encompassed experimental models with or without ALI subjected to heightened CO2 concentration and their ensuing immunomodulatory ramifications.

4.5. Results mapping

The collated data are meticulously tabulated to furnish a comprehensive descriptive synopsis, commensurate with the overarching objective and inquiry of the scoping review.

5. Conclusions

Our scoping review elucidated significant insights in experimental models, with or without lung injury, pertaining to the role of hypercapnia and its immunomediated mechanisms. This characterization delineated a compromised innate immune system capacity, alongside alterations in respiratory epithelium repair and healing. Future clinical investigations are warranted to assess the immunomediated clinical advantages of hypercapnia.

Author Contributions

Conceptualization, E.O.-R. and J.C.-G.; writing—original draft preparation, E.O.-R., J.C.-G., D.R.-B., M.B.-L., E.G.-R. and C.D.-C.; project administration, E.O.-R.; writing—review and editing, E.O.-R., J.C.-G., D.R.-B., M.B.-L., E.G.-R., J.P.-P., J.V.-T., J.E.-G., and C.D.-C. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. All authors have read and agreed to the published version of the manuscript.

Funding

Not applicable.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The data used and/or analyzed during the present study are available from the corresponding author upon reasonable request.

Acknowledgments

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

Appendix A

Table A1. Prisma-ScR checklist.
Table A1. Prisma-ScR checklist.
Section Item PRISMA-ScR checklist item Page #
Title
Title 1 Identify the report as a scoping review 1
Structured summary 2 Provide a structured abstract that includes (as applicable): background, objectives, eligibility criteria, sources of evidence, charting methods, results, and conclusions that relate to the review questions and objectives 1
Introduction
Rationale 3 Describe the rationale for the review in the context of what is already known. Explain why the review questions/objectives lend themselves to a scoping review approach. 1, 2
Objectives 4 Provide an explicit statement of the questions and objectives being addressed with reference to their key elements (e.g., population or participants, concepts, and context) or other relevant key elements used to conceptualize the review questions and/or objectives. 2
Methods
Protocol and registration 5 Indicate whether a review protocol exists; state if and where it can be accessed (e.g., a Web address); and if available, provide registration information, including the registration numbe NA
Eligibility criteria 6 Specify characteristics of the sources of evidence used as eligibility criteria (e.g., years considered, language, and publication status), and provide a rationale 10, 11
Information sources 7 Describe all information sources in the search (e.g., databases with dates of coverage and contact with authors to identify additional sources), as well as the date the most recent search was executed 11
Search 8 Present the full electronic search strategy for at least one database, including any limits used, such that it could be repeated. 11, Appendix A2
Selection of sources of evidence 9 State the process for selecting sources of evidence (i.e., screening and eligibility) included in the scoping review 11
Data charting process 10 Describe the methods of charting data from the included sources of evidence (e.g., calibrated forms or forms that have been tested by the team before their use, and whether data charting was done independently or in duplicate) and any processes for obtaining and confirming data from investigators. 11, Figure 1. PRISMA-ScR checklist.
Data ítems 11 List and define all variables for which data were sought and any assumptions and simplifications made 11
Critical appraisal of individua sources of evidence 12 If done, provide a rationale for conducting a critical appraisal of included sources of evidence; describe the methods used and how this information was used in any data synthesis (if appropriate) 11
Synthesis of results 13 Describe the methods of handling and summarizing the data that were charted. 11
Result
Selection of sources of evidence 14 Give numbers of sources of evidence screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally using a flow diagram Figure 1. PRISMA-ScR checklist.
Characteristics of sources of evidence 15 For each source of evidence, present characteristics for which data were charted and provide the citations Table 2
Critical appraisal within sources of evidence 16 If done, present data on critical appraisal of included sources of evidence (see item 12)
Results of individual sources of evidence 17 For each included source of evidence, present the relevant data that were charted that relate to the review questions and objectives. Table 2, figures 2 and 3
Synthesis of results 18 Summarize and/or present the charting results as they relate to the review questions and objectives Table 2
Discussion
Summary of evidence 19 Summarize the main results (including an overview of concepts, themes, and types of evidence available), link to the review questions and objectives, and consider the relevance to key groups 2 - 10
Limitations 20 Discuss the limitations of the scoping review process. 10
Conclusions 21 Provide a general interpretation of the results with respect to the review questions and objectives, as well as potential implications and/or next steps. 11
Funding
Funding 22 Describe sources of funding for the included sources of evidence, as well as sources of funding for the scoping review. Describe the role of the funders of the scoping review NA
Table A2. Search Strategy.
Table A2. Search Strategy.
Search number Search terms
1 Pneumonia
2 Hypercapnia
3 Acute respiratory distress syndrome (ARDS)
4 Ventilator-Associated Pneumonia (VAP)
5 Anti-Inflammatories
6 Anti-Inflammatories
7 1 AND 2 AND 3
8 4 AND 2
9 5 AND 2 AND 1

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  55. Hamacher J, Hadizamani Y, Borgmann M, Mohaupt M, Männel DN, Moehrlen U, et al. Cytokine–Ion Channel Interactions in Pulmonary Inflammation. Front Immunol [Internet]. 2018 Jan 4;8. [CrossRef]
  56. Baloğlu E, Mairbäurl H. In Search of a Sensor: How Does CO 2 Regulate Alveolar Ion Transport? Am J Respir Cell Mol Biol [Internet]. 2021 Dec;65(6):571–2. [CrossRef]
  57. Vadász I, Sznajder JI. Gas Exchange Disturbances Regulate Alveolar Fluid Clearance during Acute Lung Injury. Front Immunol [Internet]. 2017 Jul 4;8. [CrossRef]
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Figure 1. RISMA-ScR checklist.
Figure 1. RISMA-ScR checklist.
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Figure 2. Anti-inflammatory effects of hypercapnia in models experimental acute pulmonay injury. Hypercapnic acidosis attenuates the immune response and allows alveolar disruption that can allow bacterial propagation and replication. Abbreviations: ARDS: Acute Respiratory Distress Syndrome; V: Ventilation; Q: Perfusion. Designed by the Research Group in Intensive Medicine and Comprehensive Care (GRIMICI).
Figure 2. Anti-inflammatory effects of hypercapnia in models experimental acute pulmonay injury. Hypercapnic acidosis attenuates the immune response and allows alveolar disruption that can allow bacterial propagation and replication. Abbreviations: ARDS: Acute Respiratory Distress Syndrome; V: Ventilation; Q: Perfusion. Designed by the Research Group in Intensive Medicine and Comprehensive Care (GRIMICI).
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Figure 3. Anti-inflammatory effects of hypercapnia in models experimental acute pulmonay injury. A. The interaction of hypercapnia and NF-kB pathways is visualized. B. The interaction of hypercapnia with intracellular biological pathways is visualized to inactivate proinflammatory cytokines and promote apoptosis that leads to cellular damage. C. The interaction of hypercapnia in the respiratory epithelium is visualized, which entails the endocytosis of ENac and Na/K-ATPase, allowing alveolar disruption. D. Hypercapnia impairs mitochondrial dysfunction that leads to alveolar disruption and inhibits the pulmonary reparative role. Abbreviations: CO2: Carbon dioxide; O2: Oxygen; ATI: flattened alveolar type I; ATII: cuboidal alveolar type II; IκB: Inhibitor of kappa B; NF-κB: Nuclear Factor-kappa B; TNF: Tumor Necrosis Factor; Bcl-2: B-cell lymphoma 2; Bcl-xL: B-cell lymphoma-extra large protein; CXCL1: Chemokine Ligand 1; CXCL2: Chemokine Ligand 2; CXCL14: Chemokine Ligand 14; CCL28: Chemokine Ligand 28; ERK: Extracellular signal-regulated kinase; AMPK: AMP-activated protein kinase; PKC: Protein kinase C; JNK: c-Jun N-terminal kinases; AC: Adenylate cyclase; ENaC: Epithelial sodium channels; CCL2: Chemokine Ligand 2; ICAM1: Intercellular Adhesion Molecule 1; IDH2: Isocitrate dehydrogenase 2. ATP: Adenosine triphosphate. Designed by the Research Group in Intensive Medicine and Comprehensive Care (GRIMICI).
Figure 3. Anti-inflammatory effects of hypercapnia in models experimental acute pulmonay injury. A. The interaction of hypercapnia and NF-kB pathways is visualized. B. The interaction of hypercapnia with intracellular biological pathways is visualized to inactivate proinflammatory cytokines and promote apoptosis that leads to cellular damage. C. The interaction of hypercapnia in the respiratory epithelium is visualized, which entails the endocytosis of ENac and Na/K-ATPase, allowing alveolar disruption. D. Hypercapnia impairs mitochondrial dysfunction that leads to alveolar disruption and inhibits the pulmonary reparative role. Abbreviations: CO2: Carbon dioxide; O2: Oxygen; ATI: flattened alveolar type I; ATII: cuboidal alveolar type II; IκB: Inhibitor of kappa B; NF-κB: Nuclear Factor-kappa B; TNF: Tumor Necrosis Factor; Bcl-2: B-cell lymphoma 2; Bcl-xL: B-cell lymphoma-extra large protein; CXCL1: Chemokine Ligand 1; CXCL2: Chemokine Ligand 2; CXCL14: Chemokine Ligand 14; CCL28: Chemokine Ligand 28; ERK: Extracellular signal-regulated kinase; AMPK: AMP-activated protein kinase; PKC: Protein kinase C; JNK: c-Jun N-terminal kinases; AC: Adenylate cyclase; ENaC: Epithelial sodium channels; CCL2: Chemokine Ligand 2; ICAM1: Intercellular Adhesion Molecule 1; IDH2: Isocitrate dehydrogenase 2. ATP: Adenosine triphosphate. Designed by the Research Group in Intensive Medicine and Comprehensive Care (GRIMICI).
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Table 1. Study design and geographical location of the scoping review articles (in chronological order of publication by year).
Table 1. Study design and geographical location of the scoping review articles (in chronological order of publication by year).
Citacion Year Country Type of study
Vadász I 2008 Jan USA Experimental
O’Croinin DF 2008 Jul Ireland Experimental
Liu Y 2008 Aug USA Experimental
Chonghaile MN 2008 Nov Ireland Experimental
Ni Chonghaile M 2008 Dec Ireland Experimental
Nichol AD 2009 Nov Ireland Experimental
O'Toole D 2009 Nov Ireland Experimental
Wang N 2010 Feb USA Experimental
Welch LC 2010 Sep USA Experimental
Peltekova V 2010 Oct Canada Experimental
Cummins EP 2010 Oct Ireland Experimental
Vohwinkel CU 2011 Oct USA Experimental
Oliver K 2012 Apr Ireland Experimental
Contreras M 2012 Sep Ireland Experimental
Vadász I 2012 Oct USA Experimental
Lecuona E 2013 May USA Experimental
Gates KL 2013 Nov USA Experimental
Nardelli LM 2015 Jan Brazil Experimental
Casalino-Matsuda SM 2015 Apr USA Experimental
Yang W 2015 Dec China Experimental
Masterson C 2016 Apr Ireland Experimental
Horie S 2016 Dec Ireland Experimental
Gwoździńska P 2017 May Germany Experimental
Keogh C 2017 Jul Ireland Experimental
Casalino-Matsuda SM 2018 Sep USA Experimental
Cortes-Puentes GA 2019 Jan USA Experimental
Kryvenko V 2020 Feb Germany Experimental
Casalino-Matsuda SM 2021 Apr USA Experimental
Gabrielli NM 2021 Jul Germany Experimental
Kryvenko V 2021 Dec Germany Experimental
Table 2. Summary of publications on the effects of hypercapnia on host defense and respiratory epithelium.
Table 2. Summary of publications on the effects of hypercapnia on host defense and respiratory epithelium.
Author Experimental Model Secondary Injury CO2 Concentration Immunomodulatory Effect
Alteration in transcription of innate response
O'Toole et al., 2009
[22]		 In vitro: Confluent bronchial, respiratory, and alveolar A549 type II epithelial cells No 10%, 15% Hypercapnia directly inhibits NF-κB activation
Liu et al., 2008
[30]		 In vivo (rats) and In vitro: Human pulmonary microvascular endothelial cells LPS and bacterial TNF (24 hours) 5%, 10% In vitro model shows that 4 hours of hypercapnia and metabolic acidosis increase NF-κB expression
Wang N et al., 2010
[18]		 In vitro: THP-1 cells, human alveolar macrophages, RAW 264.7 mouse macrophages Bacterial LPS and TLR 5%, 9%, 12.5%, 20% Hypercapnia attenuates TNF and IL-6 mRNA induction independently of extracellular metabolic acidosis. Also, it does not affect IkBα and RelA/p65 phosphorylation
Cummins et al., 2010
[23]		 In vitro: Respiratory epithelial cells Endotoxin 5%, 10% Hypercapnia blocks IκBα phosphorylation, degradation, and p65 translocation, inactivating NF-κB
Oliver et al., 2012
[24]		 In vivo (rats) and In vitro: Alveolar epithelial A549 cells No 5%, 10% Hypercapnia promotes RelB cleavage and localization during the non-canonical signaling pathway, exerting an anti-inflammatory and immunosuppressive effect
Contreras et al., 2012
[25]		 In vivo (rats) and In vitro: Alveolar epithelial A549 cells No 5% Hypercapnia inactivates NF-κB in vivo and in vitro, maintaining cytoplasmic IκBα concentrations
Yang et al., 2015
[26]		 In vivo (rats) None CO2 ventilation: 35 - 150 mmHg Hypercapnia reduced IkBα expression and NF-κB activity
Masterson et al., 2016
[27]		 In vivo (rats) and In vitro: Alveolar epithelial cells Escherichia coli (4 hours) Inspired CO2 ventilation: 5% Hypercapnia inhibits p65 subunit translocation, reduces IκBβ intrinsic phosphorylation, IκBα concentrations, and maintains NF-κB inactivation
Horie et al., 2016
[28]		 In vitro: Bronchial and alveolar A549 cells Lung stretch (24 - 120 hours) 5%, 10% Hypercapnia blocks IκBα phosphorylation, degrades proteins, inactivating NF-κB
Keogh C et al., 2017
[29]		 In vitro: Alveolar epithelial A549 cells No 5%, 10% Hypercapnia promotes non-canonical NF-κB RelB/p100 activation, exerting an anti-inflammatory and immunosuppressive effect
Decease in innate immune response capacity
O’Croinin et al., 2008
[17]		 In vivo (rats) Escherichia coli (48 hours) Inspired CO2 ventilation: 5% Prolonged hypercapnia affects neutrophil phagocytic activity, worsening bacterial infection-induced lung injury
Liu et al., 2008
[30]		 In vivo (rats) and In vitro: Human pulmonary microvascular endothelial cells LPS and bacterial TNF (24 hours) 5%, 10% 4 hours of hypercapnia increased neutrophil adhesion and expression of ICAM1, VCAM1, E-selectin, and IL-8, exhibiting a proinflammatory effect
Chonghaile et al., 2008
[12]		 In vivo (rats): Established pneumonia Escherichia coli (6 hours) Inspired CO2 ventilation: 5% In a model of established pneumonia, hypercapnia increased TNF-α and IL-6 levels, improved airway pressures. In the presence of antibiotic therapy, it reduced bacterial count and pneumonia-induced histological injury
Ni Chonghaile et al., 2008
[31]		 In vivo (rats) Escherichia coli (6 hours) Inspired CO2 ventilation: 5% During pulmonary sepsis, hypercapnia affects neutrophil phagocytic activity, reducing bacterial death and worsening lung injury
Nichol et al., 2009
[39]		 In vivo (rats) and In vitro: Bronchial epithelial cells Endotoxin and Escherichia coli Inspired CO2 ventilation: 5% Buffered hypercapnia in the absence of metabolic acidosis does not alter phagocytic capacity and neutrophil concentration. However, it increases maximum airway pressure, exacerbating lung injury
Wang N et al., 2010
[18]		 In vitro: THP-1 cells, human alveolar macrophages, RAW 264.7 mouse macrophages Lipopolysaccharides and bacterial TLR 5%, 9%, 12.5%, 20% Hypercapnia inhibits macrophage phagocytosis
Peltekova et al., 2010
[32]		 In vivo (rats) Harmful ventilation Inspired CO2 ventilation: 0%, 5%, 12%, 25% Hypercapnia decreases TNFα levels and increases nitrotyrosine formation, enhancing lung injury
Cummins et al., 2010
[23]		 In vitro: Respiratory epithelial cells Endotoxin 5%, 10% Hypercapnia reduces proinflammatory response gene expression (CCL2, ICAM1, and TNF-α)
Oliver et al., 2012
[24]		 In vivo (rats) and In vitro: Alveolar epithelial A549 cells No 5%, 10% Hypercapnia suppresses TNF-α expression independent of pH
Gates et al., 2013
[33]		 In vivo (rats) Pseudomonas aeruginosa (96 hours) Inspired CO2 ventilation: 10% In a model of established pneumonia, hypercapnia alters neutrophil phagocytic capacity, increases bacterial load and dissemination to other organs, and reduces early cytokine response (IL-6, TNF)
Nardelli et al., 2015
[34]		 In vivo (rats) Paraquat PaCO2 ventilation: 35 - 80 mmHg Hypercapnia, independent of acidosis, reduces IL-6, IL-1β, and type III pro-collagen expression. It also decreases neutrophil count and apoptosis processes
Casalino-Matsuda et al., 2015
[35]		 In vitro: Human alveolar macrophages No 5%, 15% Hypercapnia increases anti-apoptotic factors Bcl-2, Bcl-xL, inhibiting Beclin 1 and autophagy and bacterial death
Yang et al., 2015
[26]		 In vivo (rats) None CO2 ventilation: 35 - 150 mmHg Hypercapnia attenuates TNF-α levels independent of pH
Casalino-Matsuda et al., 2018
[36]		 In vitro: Bronchial epithelial cells Lung injury (24 hours) 20% Sustained hypercapnia for 24 hours alters the regulation of immunoregulatory genes such as CXCL1, CXCL2, CXCL14, CCL28, IL-6R, and TLR4
Casalino-Matsuda et al., 2021
[37]		 In vitro: Human alveolar macrophages, RAW 264.7 mouse macrophages No 20% Hypercapnia downregulates NF-κB pathway genes, type I interferon and antiviral signaling genes, cytokines, and other associated genes
Disruption and resealing of alveolar epithelial cells
Vadász et al., 2008
[38]		 In vitro: Alveolar epithelial cells No PaCO2: 60 - 120 mmHg Hypercapnia increases AMPK overexpression, inducing PKC-ζ activation, promoting Na/K-ATPase endocytosis, and inhibiting alveolar fluid reabsorption
Nichol et al., 2009
[39]		 In vivo (rats) and In vitro: Bronchial epithelial cells Endotoxin and Escherichia coli Inspired CO2 ventilation: 5% Buffered hypercapnia, without metabolic acidosis, decreases lung cell wound repair rate
O'Toole et al., 2009
[22]		 In vitro: Confluent bronchial, respiratory, and alveolar A549 type II epithelial cells No 10%, 15% Hypercapnia decreases lung cell wound healing through a mechanism associated with direct NF-Κb activation inhibition
Welchl et al., 2010
[40]		 In vitro: Alveolar epithelial cells No 5% Hypercapnia activates ERK 1/2, promoting Na/K-ATPase endocytosis and inhibiting alveolar fluid reabsorption
Vohwinkel et al., 2011
[41]		 In vitro: Alveolar epithelial A549 cells and fibroblasts No 5% Hypercapnia increases microRNA-183 expression, downregulating isocitrate dehydrogenase 2 expression, affecting mitochondrial function and cell proliferation
Vadász et al., 2012
[42]		 In vitro: Alveolar epithelial cells No PaCO2: 60 - 120 mmHg Hypercapnia induces JNK activation, leading to Na/K-ATPase downregulation and alveolar epithelial dysfunction
Lecuona et al., 2013
[43]		 In vitro: Alveolar epithelial cells No PaCO2: 60 - 120 mmHg Hypercapnia activates soluble adenylate cyclase CO2/HCO3-sensitive, stimulating cAMP production and PKA activity, favoring Na/K-ATPase endocytosis and alveolar epithelial dysfunction
Gwoździńska et al., 2017
[44]		 In vitro: Alveolar epithelial A549 cells No 5% Hypercapnia promotes ERK/AMPK/JNK axis activation, affecting ENaC cellular activity via polyubiquitination mechanism
Cortes-Puentes et al., 2019
[45]		 In vitro: Alveolar epithelial cells No 80 Torr Hypercapnia activates soluble adenylate cyclase, delaying lung membrane resealing and alveolar epithelial cell repair
Kryvenko et al., 2020
[46]		 In vitro: Alveolar epithelial A549 and rat type II cells No 5%, 15% Hypercapnia causes Na/K-ATPase-β retention in the endoplasmic reticulum and significant reduction in the alveolar membrane
Gabrielli et al., 2021
[47]		 In vitro: Alveolar epithelial A549 cells No 5% Hypercapnia promotes ubiquitination of E3 ligase, favoring Na/K-ATPase β subunit endocytosis and degradation mediated by PKC-ζ
Kryvenko et al., 2021
[48]		 In vitro: Alveolar epithelial A549 cells No 5% Hypercapnia affects Na/K-ATPase β subunit in the endoplasmic reticulum and basal membrane
Abbreviations: cAMP: Cyclic adenosine monophosphate; PKA: Protein kinase A; ERK: Extracellular signal-regulated kinase; AMPK: AMP-activated protein kinase; JNK: c-Jun N-terminal kinases; ENaC: Epithelial sodium channels; PKC: Protein kinase C; NF-κB: Nuclear Factor-kappa B; PKC: Protein kinase C; ERK: Extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinases; CCL2: Chemokine Ligand 2; ICAM1: Intercellular Adhesion Molecule 1; VCAM1: molécula de citoadhesión vascular 1; TNF: Tumor Necrosis Factor; IL-1: Interleukin 1; IL-6: Interleukin 6; IL-8: Interleukin 8; Bcl-2: B-cell lymphoma 2; Bcl-xL: B-cell lymphoma-extra large protein; CXCL1: Chemokine Ligand 1; CXCL2: Chemokine Ligand 2; CXCL14: Chemokine Ligand 14; CCL28: Chemokine Ligand 28; TLR4: Toll-Like Receptor 4; IκB: Inhibitor of kappa B; LPS: Lipopolysaccharides; TLR: Toll-Like Receptor; mRNA: Messenger Ribonucleic Acid.
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