Infection-induced lung injury is worsened after renal buffering of hypercapnic acidosis

Nichol, Alistair; O'Cronin, Donall F.; Howell, Katharine A.; Naughton, Finola; O'Brien, Sorca; Boylan, John F.; O'connor, Clare M.; O’Toole, Daniel; Laffey, John G.; McLoughlin, Paul

doi:10.1097/ccm.0b013e3181b028ce

Cited by 45 publications

(45 citation statements)

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“…In Drosophila, increased susceptibility to bacterial infection at elevated CO 2 is independent of pH change (9). Furthermore, increased susceptibility to infection persists in rats with normal renal buffering of hypercapnic-acidosis (27), which in the absence of acidosis is suggestive of pH-independent, CO 2 -dependent immunosuppression. This study suggests the existence of an intracellular CO 2 sensor that is associated with anti-inflammatory and immunosuppressive signaling, is independent of intracellular and extracellular pH, and could account for the above clinical observations.…”

Section: Discussionmentioning

confidence: 99%

“…Similarly, hypercapnic acidosis attenuates endotoxin-induced acute lung injury, supporting a generally anti-inflammatory effect of CO 2 (8). Furthermore, elevated CO 2 increases mortality in Drosophila exposed to pathogens and augments infection-induced injury in rats, indicating a role for CO 2 -sensing in suppression of innate immunity (9,10). NF-kB is a key transcriptional regulator of inflammation and innate immunity (11).…”

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confidence: 89%

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NF-κB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells

Cummins

Oliver

Lenihan

et al. 2010

The Journal of Immunology

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Section: Discussionmentioning

confidence: 99%

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confidence: 89%

NF-κB Links CO2 Sensing to Innate Immunity and Inflammation in Mammalian Cells

Cummins

Oliver

Lenihan

et al. 2010

The Journal of Immunology

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“…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]. Hypercapnic acidosis also inhibits phagocytosis of opsonized polystyrene beads by human alveolar macrophages, although the levels of CO 2 utilized to demonstrate this eff ect were well beyond the range encountered clinically [19].…”

Section: The Cellular Innate Immune Responsementioning

confidence: 94%

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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“…These effects seem to be due in part to the anti-inflammatory effects of hypercapnia, including attenuation of neutrophil function, reduction in free radicals, decreased oxidantinduced tissue damage, and reduction in the levels of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-8 [20]. However, some of these beneficial effects were likely caused by systemic acidosis rather than hypercapnia per se, because buffering of respiratory acidosis worsened experimental lung injury [21]. Recent studies confirm that CO 2 can also act as a signaling molecule via pH-independent mechanisms, leading to deleterious effects in the lung.…”

Section: Cellular and Metabolic Effectsmentioning

confidence: 99%