Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury*

O’Croinin, Donall; Nichol, Alistair; Hopkins, Natalie; Boylan, John F.; O'Brien, Sorca; O'connor, Clare M.; Laffey, John G.; McLoughlin, Paul

doi:10.1097/ccm.0b013e31817d1b59

Cited by 121 publications

(126 citation statements)

References 45 publications

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“…Thus, hypercapnia reduces resistance to some bacterial infections. These results are consistent with hypercapnic acidosis increasing lung bacterial load in a rat pneumonia model (8), and with hypercapnic hypoxia increasing bacterial load in infected marine invertebrates (15).…”

Section: Resultssupporting

confidence: 78%

“…However, when pathogens are present, as in patients with COPD or cystic fibrosis, immune suppression by hypercapnia could increase susceptibility to, or exacerbate consequences of, bacterial infections. Experimental support of this possibility is provided by O'Croinin et al (8) who recently showed that in a bacterial pneumonia model, rats exposed to 5% CO 2 had higher lung bacterial counts and more structural damage than normocapnic controls. Together, the Drosophila and rat results suggest that hypercapnia is not simply a marker of disease status, but rather that it can actively contribute to the progression of infection.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro and animal studies have shown that hypercapnia can suppress mammalian inflammatory responses (6)(7)(8), including NF-B-regulated cytokine production (9)(10)(11), which could contribute to the poor outcomes of patients with COPD and CF who frequently suffer from both hypercapnia and bacterial lung infections (12,13). Hypercapnic immune suppression may be evolutionarily conserved because hypercapnia, in combination with hypoxia, also suppresses innate immune responses in shrimp, oysters, and crabs (14)(15)(16).…”

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confidence: 99%

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Elevated CO₂suppresses specific Drosophila innate immune responses and resistance to bacterial infection

Helenius

Krupinski

Turnbull

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

123

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Elevated CO2 levels (hypercapnia) frequently occur in patients with obstructive pulmonary diseases and are associated with increased mortality. However, the effects of hypercapnia on non-neuronal tissues and the mechanisms that mediate these effects are largely unknown. Here, we develop Drosophila as a genetically tractable model for defining non-neuronal CO 2 responses and response pathways. We show that hypercapnia significantly impairs embryonic morphogenesis, egg laying, and egg hatching even in mutants lacking the Gr63a neuronal CO 2 sensor. Consistent with previous reports that hypercapnic acidosis can suppress mammalian NF-B-regulated innate immune genes, we find that in adult flies and the phagocytic immune-responsive S2* cell line, hypercapnia suppresses induction of specific antimicrobial peptides that are regulated by Relish, a conserved Rel/NF-B family member. Correspondingly, modest hypercapnia (7-13%) increases mortality of flies inoculated with E. faecalis, A. tumefaciens, or S. aureus. During E. faecalis and A. tumefaciens infection, increased bacterial loads were observed, indicating that hypercapnia can decrease host resistance. Hypercapnic immune suppression is not mediated by acidosis, the olfactory CO 2 receptor Gr63a, or by nitric oxide signaling. Further, hypercapnia does not induce responses characteristic of hypoxia, oxidative stress, or heat shock. Finally, proteolysis of the Relish IB-like domain is unaffected by hypercapnia, indicating that immunosuppression acts downstream of, or in parallel to, Relish proteolytic activation. Our results suggest that hypercapnic immune suppression is mediated by a conserved response pathway, and illustrate a mechanism by which hypercapnia could contribute to worse outcomes of patients with advanced lung disease, who frequently suffer from both hypercapnia and respiratory infections.COPD ͉ hypercapnia ͉ Relish ͉ NF-B ͉ Gr63a

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Section: Resultssupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Elevated CO₂suppresses specific Drosophila innate immune responses and resistance to bacterial infection

Helenius

Krupinski

Turnbull

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

123

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“…Putative mediators of lung injury shown to be attenuated by therapeutic hypercapnia in these models have included inflammatory cell influx (37,45,72), proinflammatory cytokines (14,38,72), and oxidative stress (31,38,52,72). However, several studies have also indicated the potential for hypercapnia to worsen lung injury (41,53,54) and to potentially cause an increase in inflammation in the noninjured lung (2,45), highlighting the need for further study. Our aim therefore was to examine effects of therapeutic hypercapnia in a new rat model with similarities to human BPD (47), secondary to bleomycin exposure.…”

mentioning

confidence: 99%

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

Sewing

Kantores

Ivanovska

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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Sewing AC, Kantores C, Ivanovska J, Lee AH, Masood A, Jain A, McNamara PJ, Tanswell AK, Jankov RP. Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-␣. Am J Physiol Lung Cell Mol Physiol 303: L75-L87, 2012. First published May 11, 2012; doi:10.1152/ajplung.00072.2012.-Bleomycin-induced lung injury is characterized in the neonatal rat by inflammation, arrested lung growth, and pulmonary hypertension (PHT), as observed in human infants with severe bronchopulmonary dysplasia. Inhalation of CO2 (therapeutic hypercapnia) has been described to limit cytokine production and to have anti-inflammatory effects on the injured lung; we therefore hypothesized that therapeutic hypercapnia would prevent bleomycin-induced lung injury. Spontaneously breathing rat pups were treated with bleomycin (1 mg/kg/d ip) or saline vehicle from postnatal days 1-14 while being continuously exposed to 5% CO2 (PaCO 2 elevated by 15-20 mmHg), 7% CO2 (PaCO 2 elevated by 35 mmHg), or normocapnia. Bleomycin-treated animals exposed to 7%, but not 5%, CO2, had significantly attenuated lung tissue macrophage influx and PHT, as evidenced by normalized pulmonary vascular resistance and right ventricular systolic function, decreased right ventricular hypertrophy, and attenuated remodeling of pulmonary resistance arteries. The level of CO2 neither prevented increased tissue neutrophil influx nor led to improvements in decreased lung weight, septal thinning, impaired alveolarization, or decreased numbers of peripheral arteries. Bleomycin led to increased expression and content of lung tumor necrosis factor (TNF)-␣, which was found to colocalize with tissue macrophages and to be attenuated by exposure to 7% CO2. Inhibition of TNF-␣ signaling with the soluble TNF-2 receptor etanercept (0.4 mg/kg ip from days 1-14 on alternate days) prevented bleomycin-induced PHT without decreasing tissue macrophages and, similar to CO2, had no effect on arrested alveolar development. Our findings are consistent with a preventive effect of therapeutic hypercapnia with 7% CO2 on bleomycin-induced PHT via attenuation of macrophage-derived TNF-␣. Neither tissue macrophages nor TNF-␣ appeared to contribute to arrested lung development induced by bleomycin. That 7% CO2 normalized pulmonary vascular resistance and right ventricular function without improving inhibited airway and vascular development suggests that vascular hypoplasia does not contribute significantly to functional changes of PHT in this model. carbon dioxide; inflammation; neonatal lung injury BRONCHOPULMONARY DYSPLASIA (BPD) is a chronic pneumopathy affecting extremely premature infants who frequently require supplemental oxygen and/or mechanical ventilation. The incidence of BPD is inversely proportional to the gestational age at which infants are born, with an incidence approaching 60% in the smallest survivors (4). The cardinal feature of BPD, as observed in the current era, is an inhibition or arrest of alveolar and ...

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“…Th e potential for hypercapnic acidosis to inhibit neutrophil chemotaxis and migration to the site of injury has been confi rmed in vivo, where hypercapnic acidosis inhibits pulmonary neutrophil infi ltration in response to endotoxin instillation [11]. Hypercapnic acidosis directly impairs neutrophil phagocytosis in vitro [23]. Th is inhibitory eff ect appears to be a function of the acidosis per se, with buff ering restoring neutrophil phagocytosis [24].…”

Section: The Cellular Innate Immune Responsementioning

confidence: 99%

Can ‘Permissive’ Hypercapnia Modulate the Severity of Sepsis-induced ALI/ARDS?

Curley

Hayes

Laffey

2011

Annual Update in Intensive Care and Emergency Medicine 2011

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Ventilatory strategies that reduce lung stretch by reducing tidal and minute ventilation, which results in a 'permissive' hypercapnic acidosis, improve outcome in patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) [1,2]. Reassuringly, evidence from clinical studies attests to the safety and lack of detrimental eff ects of hypercapnic acidosis [2]. Of parti cu lar importance, a secondary analysis of data from the ARDSnet tidal volume study [1] demonstrated that the presence of hypercapnic acidosis at the time of randomization was associated with improved patient survival in patients who received high tidal volume ventilation [3]. Th ese fi ndings have resulted in a shift in paradigms regarding hypercapnia -from avoidance to tolerancewith hypercapnia increasingly permitted in order to realize the benefi ts of low lung stretch. Conse quently, low tidal and minute volume ventilation and the accompanying `permissive' hypercapnia are now the standard of care for patients with ALI/ARDS, and are increasingly used in the ventilatory management of a diverse range of diseases leading to acute severe respira tory failure, includ ing asthma and chronic obstructive pulmonary disease.Th e infl ammatory response plays a central role in the pathogenesis of injury and in the repair process in ALI/ ARDS [4]. Infl ammation is a highly conserved process in evolution, which is essential for survival. It functions to resolve the injurious process, facilitate repair, and return the host to a state of homeostasis. Th e ideal infl ammatory process is rapid, causes focused destruction of pathogens, yet is specifi c and ultimately self-limiting [5]. In contrast, when the infl ammatory response is dysregulated or persistent, this can lead to excessive host damage, and contribute to the pathogenesis of lung and systemic organ injury, leading to multiple organ failure and death. Th e potential for hypercapnia and/or its associated acidosis to potently inhibit the immune response is increasingly recognized [6,7]. Where the host immune response is a major contri bu tor to injury, such as in non-septic ALI/ ARDS, these eff ects would be expected to result in potential benefi t. Th is has been demonstrated clearly in relevant pre-clinical ALI/ARDS models, where hypercapnic acidosis has been demonstrated to attenuate ALI induced by free radicals [8], pulmonary [9] and systemic ischemia-reperfusion [10], pulmonary endo toxin instillation [11], and excessive lung stretch [12]. Th e protective eff ects of hypercapnic acidosis in these models appear due, at least in part, to its anti-infl ammatory eff ects.Th e eff ects of hypercapnia in sepsis-induced lung injury, where a robust immune response to microbial infec tion is central to bacterial clearance and recovery, is less clear. Of concern, severe sepsis-induced organ failure, whether pulmonary or systemic in origin, is the leading cause of death in critically ill adults and children [13]. Sepsis-induced ARDS is associated with the highest mortality rates. Evidence sugges...

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Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury*

Cited by 121 publications

References 45 publications

Elevated CO₂suppresses specific Drosophila innate immune responses and resistance to bacterial infection

Elevated CO₂suppresses specific Drosophila innate immune responses and resistance to bacterial infection

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

Can ‘Permissive’ Hypercapnia Modulate the Severity of Sepsis-induced ALI/ARDS?

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Sustained hypercapnic acidosis during pulmonary infection increases bacterial load and worsens lung injury*

Cited by 121 publications

References 45 publications

Elevated CO2suppresses specific Drosophila innate immune responses and resistance to bacterial infection

Elevated CO2suppresses specific Drosophila innate immune responses and resistance to bacterial infection

Therapeutic hypercapnia prevents bleomycin-induced pulmonary hypertension in neonatal rats by limiting macrophage-derived tumor necrosis factor-α

Can ‘Permissive’ Hypercapnia Modulate the Severity of Sepsis-induced ALI/ARDS?

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Elevated CO₂suppresses specific Drosophila innate immune responses and resistance to bacterial infection

Elevated CO₂suppresses specific Drosophila innate immune responses and resistance to bacterial infection