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

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.