CURRENTOPINION Hypercapnia: clinical relevance and mechanisms

wskib, and Brian P. Kavanaghb,c

nducted to illustrate the effects of hypercapnia in aunderlying these effects. The aim of this review is toe r

dret imof

cer.

ideapniat

carbon dioxide, hypercapnia, hypertension, ischemia, pneumonia

INTRODUCTION

The use of lower tidprotective ventilatiorespiratory distress sdocumented to showmortality rates [1].leads to an increase(hypercapnia), andresulting is termed hFrom studies spanninbeen associatedwith iof patients with acutealso with favorableischemia and brainmucosal injury due tious in-vivo, ex-vivo, and in-vitro models of acutelung injury, there has also been soharmful effects of HCA, evenwhenoutweihighlight and interpret informfrom mwithwleadin

Physiology and Experimental Medicine and Departments of CriticalCare Medicine and Anesthesia, Hospital for Sick Children, University

to.ca

1070-52

REVIEWhatwe already know, discuss their impact ing toward the routine use of hypercapnia.

Curr Opin Crit Care 2015, 21:712

DOI:10.1097/MCC.0000000000000164

95 Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved. www.co-criticalcare.comore recent experimental series and, takenAvenuutoron Copyright 20ts [9]. Here, weation obtained

Medicine, Hospital for Sick Children, University of Toronto, 555 Universitye, Toronto, ON M5G 1X8, Canada. E-mail: brian.kavanagh@ghed by the beneficial effecCorrespondence to Dr Brian P. Kavanagh, Department of Critical Careme evidence forthey seem to be

of Toronto, Toronto, Ontario, Canadaal volumes as a method ofn in patients with acuteyndrome (ARDS) has beena significant reduction in

This protective ventilationin arterial carbon dioxide

the associated drop in pHypercapnic acidosis (HCA).g the last 30 years, HCA hasmprovement in the outcomelung injury/ARDS [26] andeffects in acute myocardialinjury [7] as well as gut

o sepsis [8]. However, in var-

VASCULAR EFFECTS

Recent studies have focused on the pulmonary andsystemic vasculature. Hypercapnia has previouslybeen shown to reverse hypoxia-induced pulmonaryhypertension in adult and neonatal rats [10,11], anda number of recent publications have recapitulatedthese important effects with the aim of decipheringunderlying mechanisms.

In an infant rat model of right ventricular dys-function induced by inhaled nitric oxide andhypoxia, hypercapnia was shown to normalize ven-tricular function by modulating interleukin-1 [12].

aDepartment of Anesthesia, Keenan Research Centre for BiomedicalScience, St. Michaels Hospital, University of Toronto, bProgram in

cKeywordsof action

Claire Mastersona, Gail Otulako

Purpose of reviewMultiple clinical and laboratory studies have been corange of injuries, and to understand the mechanismshighlight and interpret information obtained from thesclinical context.

Recent findingsIn the last decade, several important articles have adinteracts in critical illness states. Among them the moscritical illness and include the effects and mechanismsinfection, inflammation, diaphragm dysfunction, andinsights that apply to multiple aspects of critical illness

SummaryExperiments involving hypercapnia have covered a wsuccess. It is becoming evident that deliberate hypercexcept wherever necessitated to avoid ventilator-assocthe molecular mechanisms must be established.15 Wolters Kluwer Heaecent reports and discuss how they may inform the

ssed key elements of how carbon dioxideportant insights relate to how hypercapnia affectscarbon dioxide in pulmonary hypertension,ebral ischemia. In addition, we discuss molecular

range of illness models with varying degrees ofia in the clinical setting should seldom be used,ed lung injury. A more complete understanding oflth, Inc. All rights reserved.

Here, hthat, ingulatioreactiveoxia-in

Anoinjury iof inhapulmoncarbonmonaryimprovmarkerexposucoveredassociaproteinished a

Bleapeuticinjury igeneratimentableomydioxidelung fuphagehyperteinducepulmonintegritincreasand thi

A chealthycapnia

in mean arterial pressure (MAP). Hypercapnia (5%carbon dioxide in air) was shown to impair the con-trol of blood flow velocity during steady state

asnsraedlercect

U

iouia in bacterial pneumonia, with apparentlylicectntrcmis

osie inoctericnceinonmmrcnfllunspleurseeddom

KEY POINTS

Neutrophil phagocytosis and oxidative reactions inpulm

Hypeischeantia

HypecAM

cAMsensiimpa

An imhypecarblung

Respiratory system

8 wypercapnia inhibited interleukin-1 secretionturn, reduced nitric oxide synthase 2 upre-

n and therefore lessened the generation ofnitrogen species that contribute to hyper-

duced pulmonary vascular remodeling.ther study using the same model of lungnvestigated the effects of two different levelsled carbon dioxide (7 and 10%) on establishedary hypertension [13]. Addition of inhaleddioxide to chronic hypoxia attenuated pul-hypertension; this was manifested as

ements in hemodynamic and structurals of pulmonary hypertension compared tore to hypoxia alone. In this case, it was dis-that inhaled carbon dioxide inhibited Rho-

ted protein kinase; thus, Rho-associatedkinase-mediatedvasoconstrictionwasdimin-nd pulmonary hypertension ameliorated.omycin is not only an important chemother-

increditiocerebventmiddhypeprot

PNE

Prevcapnconfprotin cohypepneuworkocyttissuphaggrea

NactioinduNOSpulminflahypeproithethemiliadvestratPseu

onary sepsis are impaired by hypercapnia.

rcapnia protects against central nervous systemmia by mediating levels of proapoptotic Bax andpoptotic B-cell CLL/lymphoma-2.

rcapnia modulates cytoskeletal remodeling viaP induction of a-adductin activation.

P pooling has been suggested in cells that aretive to increased bicarbonate levels; this may havect on buffering HCA.

portant sheddase, ADAM-17 is impaired byrcapnia demonstrating a new pathway by whichon dioxide is anti-inflammatory in stretch-inducedinjury. Copyright 2015 Wolters Kluwer Health

but also important as a contributor to lungn some critically ill patients. It is also used toe lung inflammation and fibrosis for exper-l models of critical illness. In experimentalcin-induced lung injury, inhaled carbonwas shown to ameliorate deterioration ofnction, in addition to attenuating macro-influx and the development of pulmonarynsion [14]. In pulmonary hypertensiondbychronichypoxia,hypercapnia attenuatedary hypertension but preserved endothelialy [15]. Importantly, attempts to buffer HCAed inducible nitric oxide synthase activity,s in turn increased endothelial permeability.linical study by Perry et al. [16] recruited 15volunteers to examine the effects of hyper-

in steady state, nonpharmacological increases

inhaledBacteritrophillevelspneum

NONIN

The poon ventilator-induced lung injury (VILI) are promis-ing. Peldemoninflammtime)-dcontroleffect opressed

ww.co-criticalcare.com, Inc. All rights reserved.

tekova et al. [23] in amousemodel ofVILI strated that hypercapnia attenuates theatory response; this occurred in a dose (and

ependent manner, without adverse effects inanimals. They suggested that the positivef hypercapnia might be a result of the sup-production of the COX-2 protein.

Volume 21 Number 1 February 2015ting results. Hypercapnia was shown to beive in early Escherichia coli infection [17,18];rast, another study reported that prolongedapnia worsened outcome in longer-termonia [19]. The overall synthesis from thisthat hypercapnia impairs neutrophil phag-s; while in the short term, this results in lessjury, in the longer term, such impairment ofytosis causes increased bacterial load and aburden of disease.hol et al. [20] have reported an antioxidantof hypercapnia. In a rat model of endotoxin-d lung injury, with and without a nonspecifichibitor, hypercapnia was shown to decreaseary oxidative reactions during establishedation. In a study of the effects of therapeutic

apnia in endotoxin-induced lung injury,ammatory responses were enhanced ings; however, the opposite was shown ineen where an anti-inflammatory cytokinewas observed [21]. More recently, theeffects of hypercapnia have been demon-in amousemodel of pneumonia induced byonas aeruginosa [22]; here, high levels ofcarbon dioxide led to increased mortality.

al load was increased in the lungs and neu-phagocytosis was decreased, and cytokinewere reduced in early but not prolongedonia.

FECTIVE ACUTE LUNG INJURY

tential for beneficial effects of hypercapniaes in MAP, whereas in normocapnic con-, increases inMAP lead to a decrease inmiddlel artery blood velocity, and hypercapnia pre-such autoregulation. Such maintenance ofcerebral artery blood velocity suggests thatapnia impairs the regulatory mechanism thats against induced hypertension.

MONIA

s studies have examined the effects of hyper-

ea

Using an isolated lung model of severe VILI,Kapetanakis et al. [24] have compared the effectsof respiratory vs. metabolic acidosis. They reportedthat bo(inducelung ed

Anin VILIby Concapniaanti-infvitro anited thinterleu

AltVILI, mdysfunction in the diaphragm. An experimentalstudy iagainstmyosincomparfactor-achemophragm

Fuccomparpermittwith 84ml/kgsuringlwhich akg), dida surfac

FindegranhistamresponThe meffect wdecreaspoint tbon dio

ISCHE

Severe,inspiregrowthleads totive effreactivhigh lein neon

Thetigatedmemor

central nervous system ischemia [30]. Hypercapniaimproved both conditions via antiapoptoticmechan-isms. Levels of proapoptotic Bax (andantiapoptotic B-

Lassedysioalvderfuerrcntsm

factor kphBa

LE

iouims oerrcpol-r1nuco pr ot hontoboinlungs. This may ultimately be an importantt

osiyndeasinr vranscrn afibonppan Naw

Hypercapnia: clinical relevance and mechanisms of action Masterson et al.

1070-529 Copyright 2015 Wolters Kluwer H

n rats suggests that hypercapnia may protectthis problem [26]. Here, diaphragmmyofiberconcentration was significantly increaseded with controls; in addition, tumor necrosis, interleukin-1b, and keratinocyte-derivedkines were all significantly decreased in dia-homogenates of hypercapnia animals.hs et al. [27] performed an interesting studying progressively lower tidal volumes whileing the resultant hypercapnia. Compared10ml/kg, reductions in tidal volume belowdid not provide additional protection; reas-

y, the severe hypercapnia (i.e., 160 mmHg),rose at extremely low tidal volume (i.e., 2ml/not reverse the protection. The study utilizedtant-depletion rabbit model of ARDS.ally, carbon dioxide preexposure blocksulation ofmast cells and significantly reducesine release implicated in allergic rhinitis inse to stimulation by compound 48/80 [28].echanism of action behind this antiallergyas demonstrated to be in correlation with ae in intracellular calcium levels. This mayoward a possible mechanism by which car-xide exerts some of its effects.

MIA

sustained hypercapnia in newborn rats (10%d carbon dioxide) appears to impair brainby increasing nitrative stress, which, in turn,microvascular degeneration [29]. This nega-ect was not seen in animals treated withe nitrogen species inhibitors showing thatvels of carbon dioxide causes nitrative stressatal brain development.effectsof therapeutichypercapniawere inves-in a rodent model, where impaired spatialy and sensorimotor function was induced by

phosof Ik

MO

PrevmaylevelFurthhypetranssignaFig.showprodled tulato

Ipulmtivebicarandfusedissueacid

Hdepedecrsuchoccuits ttran

Ioniccarbgroucomsis oIKK-

5 Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.th respiratory acidosis andmetabolic acidosisd by HCl) were equally effective in reducingema.important study of the effects of hypercapnia and possible mechanisms was conductedtreras et al. [25]. Here, the effects of hyper-onmoderate and severe VILIwere shown tobelammatory, and were overall beneficial. In-alysis demonstrated that hypercapnia inhib-e NF-kB pathway, thereby reducing levels ofkin-8andNF-kB-driven luciferaseproduction.hough not conventionally considered to beechanical ventilation can induce significant

cell Cincreexpo

Hperfucheotaterepebarrihypelatiomenischelth, Inc. All rights reserved.

o consider when attempting to buffer thes resulting from increased hypercapnia.percapnia has been shown to inhibit NF-kB-ent cytokines and, perhaps consequentially,e macrophage phagocytosis [40]. However,hibition of cytokine production does notia blockade of either NF-kB activation orslocation, and appears to occur via otheription factors [40].study by Cummins et al. [35], mouse embry-roblast cells were exposed to 0.03% or 10%dioxide, with or without pH-buffering. Thealso conducted graded pH experiments tore effects of hypercapnic andmetabolic acido-F-kB activity. Here, nuclear translocation ofas independent of O2 concentration, but was

www.co-criticalcare.com 9L/lymphoma-2) proteins were decreased (anded, respectively) in brain tissues of animalsto hypercapnia.

percapnia improvedlung injury indices suchasn pressure elevation, lung wet weight, bron-eolar lavage protein concentration, and lac-hydrogenase, in the setting of ischemiasion [6]. Filtration coefficient, an index ofintegrity, was also reduced in the setting ofapnia. This study also documented the corre-between hypercapnia-associated improve-and NF-kB inhibition, via a decrease inia-reperfusion-induced inhibitor of nuclearappa-B kinase subunit alpha/beta (IKK-a/b)orylation that, in turn, prevented degradationand NF-kB activation and translocation.

CULAR MECHANISMS

s studies have pointed out that hypercapniapair alveolar fluid clearance by decreasing thef Na,K-ATPase on plasmamembranes [31,32].investigations by this group have shown thatapnia induces endocytosis of the Na,K-ATPaserter [33] and this occurs via an extracellular-egulated kinase-regulated pathway [34] (see[3437,38

&&

,39]). Most recently, it has beenthat this is dependent on cyclic AMP (cAMP)tion; cAMP activated PKA-Ia, which, in turn,hosphorylation of a-adductin, a known reg-f Na,K-ATPase endocytosis [37].as been suggested that pools of cAMP exist inary microvessels, and such pools are sensi-bicarbonate [38

&&

]. Indeed, addition ofnate decreased transendothelial resistancecreased filtration coefficient in isolated per-

dependcarbonsame eshownembryosacchargroup [kB pathsubseqditionswere infering c

A rpointedinhibit(MAPK

7

CO2

FIGURE

CarbonimpairinNa,K-ATinducedstretch-in

Respiratory system

10PKA

cAMP

sACLPS

ERK 1/2

Na, K

-

ATPa

se

TLR4

C

P

PP

ADAM-1Stretch

Endocytosis

-Adducin

CO2

HCO3

RelB Copyright 2015 Wolters Kluwer Health

ent on carbondioxide concentration, and thedioxide effect was rapidly reversible. In thexperimental series, hypercapnia was alsoto inhibit p65 translocation in mousenic fibroblast cells in response to lipopoly-ide injury. In a further study by the same36], RelB a protein of thenoncanonicalNF-way was shown to undergo cleavage anduent translocation to the nucleus under con-of increased carbon dioxide; these effectsdependent of pH changes induced by buf-ell culture media.ecent article by Otulakowski et al. [39] hastoward a mechanism whereby hypercapnia

s p44/42 mitogen activated protein kinase) activation. Activation of p44/42 MAPK

correlainjuryfactor rent onsheddinHypercand thumal grrodentStretchreceptoshownlung m

Thedioxideand hu

Sur

Translocation

Nuc

leus

Cyt

opla

sm

leavage

p65

RelB

CO2

CO2

RelB

1. Schematic representation of the recently established intracelludioxide has been shown to confer positive anti-inflammatory effecg the translocation of p65 [35,36]. Carbon dioxide has also beenPase transporter [34,37,38&&] leading to reduced edema clearaninjury was shown to be decreased after carbon dioxide exposureduced inflammation [39].

www.co-criticalcare.comPKC

P

P44/42MAPK

EGFR

P

LigandLigand, Inc. All rights reserved.

tes with the degree of stretch-induced lung[41] and is mediated via epidermal growtheceptor activity [42]. This, in turn, is depend-the binding of endogenous ligands whoseg is induced by a sheddase ADAM-17 [43].apnia was shown to prevent ligand sheddings prevent downstream activation of epider-owth factor receptor and p44/42 MAPK inalveolar epithelial cells [40] (see Fig. 1).-induced shedding of tumour necrosis factorr (another ADAM-17 substrate) was alsoto be reduced in an isolated perfused mouseodel of injury.cellular mechanisms of action of carbonin cerebral microvascular endothelial cellsman fetal astrocytes have shed light on

Inflammation

vival, proliferation, growth

p65

lar molecular responses to elevated carbon dioxide.ts by increasing the translocation of RelB anddemonstrated to increase the endocytosis of the

ce from injured lungs. P44/42 activation by stretch-via inhibition of the sheddase ADAM-17 reducing

Volume 21 Number 1 February 2015

ea

interactions with nitrogen-derived free radicalmechanisms [44]. The production of nitric oxideby these cell types is increased in hypercapnia(and decreased in hypocapnia) during stable neutralpH leve

GAST

UsingaSchwarhypercacanine oxygenationof thesplanchendangtic andsplanchnicmucosal oxygenation. However, intraoper-ative hcolon rto prev

CONC

In condevelopillnessmodelsnovelmto bettein terms of organ and molecular-specific mechan-isms, wlearned

Ackno

None.

Financ

The worthe Canthe Dr G

Confli

There a

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ter foiva A

functio32. Lecuo

g abe tr

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1070-529 Copyright 2015 Wolters Kluwer H

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lunsin

5 Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.cts of interest

re no conflicts of interest.

ENCES AND RECOMMENDEDINGparticular interest, published within the annual period of review, haveighted as:cial intereststanding interest

tion with lower tidal volumes as compared with traditional tidal volumes forlung injury and the acute respiratory distress, syndrome. The Acuteatory Distress Syndrome Network. N Engl J Med 2000; 342:13011308.gKG,Walsh J,Henderson S, JacksonR.Low mortality rate in adult respiratorys syndrome using low-volume, pressure-limited ventilation with permissive

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ial support and sponsorship

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sio19. O

duC

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24. Kaypercapnia in patients undergoing electiveesection was shown to have little or no abilityent surgical site infection [46].

LUSION

clusion, this article reviews key researchments in the study of hypercapnia in criticaland describes many effects in experimentalof human disease, along with exploring keyolecular mechanisms of effect. As our abilityr characterize critical illness states improves,

13. PeathyPh

14. SeblphPh

15. KesyRe

16. Pece

17. Niattronic region is a risk factor of hemorrhage anders mucosal barrier function. Here, prophylac-therapeutic hypercapnia appeared to preserve

2711. Ka

chPh

12. Dupnia, induced by reducedmodel of hemorrhage.Hypols.

ROINTESTINAL IMPACT

ventilatedcaninemodelofgastrichemorrhage,tges et al. [45] aimed to determine the effects of

tidal volumes, in a

6. Winj

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res C, McNamara PJ, Teixeira L, et al. Therapeutic hypercapnia preventsc hypoxia-induced pulmonary hypertension in the newborn rat. Am Jl Lung Cell Mol Physiol 2006; 291:L912L922.

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chi F, Ghofrani HA, Schermuly RT, et al. Effects of hypercapnia and NOse inhibition in sustained hypoxic pulmonary vasoconstriction. Respir012; 13:7.BG, Lucas SJ, Thomas KN, et al. The effect of hypercapnia on statical autoregulation. Physiol Rep 2014; 2:e12059.onghaile M, Higgins BD, Costello JF, Laffey JG. Hypercapnic acidosisates severe acute bacterial pneumonia-induced lung injury by a neu--independent mechanism. Crit Care Med 2008; 36:31353144.haile MN, Higgins BD, Costello J, Laffey JG. Hypercapnic acidosisates lung injury induced by established bacterial pneumonia. Anesthe-y 2008; 109:837848.inin DF, Nichol AD, Hopkins N, et al. Sustained hypercapnic acidosispulmonary infection increases bacterial load and worsens lung injury.

are Med 2008; 36:21282135.l AD, OCronin DF, Naughton F, et al. Hypercapnic acidosis reducesive reactions in endotoxin-induced lung injury. Anesthesiology 2010;16125.ian FM, Leoncio M, Torbati D, et al. Therapeutic hypercapnia enhancesammatory response to endotoxin in the lung of spontaneously breathingrit Care Med 2011; 39:14001406.KL, Howell HA, Nair A, et al. Hypercapnia impairs lung neutrophiln and increases mortality in murine pseudomonas pneumonia. Am JCell Mol Biol 2013; 49:821828.

ova V, Engelberts D, Otulakowski G, et al. Hypercapnic acidosis intor-induced lung injury. Intensive Care Med 2010; 36:869878.anakis T, Siempos II, Metaxas EI, et al. Metabolic acidosis may be astive as hypercapnic acidosis in an ex-vivo model of severe ventilator-d lung injury: a pilot study. BMC Anesthesiol 2011; 11:8.ras M, Ansari B, Curley G, et al. Hypercapnic acidosis attenuatestion-induced lung injury by a nuclear factor-kappaB-dependent me-m. Crit Care Med 2012; 40:26222630.kens WJ, van Hees HW, Kox M, et al. Hypercapnia attenuates ventilator-

d diaphragm atrophy and modulates dysfunction. Crit Care 2014; 18:R28.H, Mendler MR, Scharnbeck D, et al. Very low tidal volume ventilationssociated hypercapniaeffects on lung injury in a model for acutetory distress syndrome. PloS One 2011; 6:e23816.

r JW, Masterson CG, Durham PL. Treatment of mast cells with carbone suppresses degranulation via a novel mechanism involving repressioneased intracellular calcium levels. Allergy 2011; 66:341350.e JC, Kooli A, Hou X, et al. Sustained hypercapnia induces cerebralascular degeneration in the immature brain through induction of nitrative. Am J Physiol Regul, Integr Comp Physiol 2010; 298:R1522R1530.Zhao M, Yang W, et al. Neuroprotective effects of therapeutic hypercapniatial memory and sensorimotor impairment via antiapoptotic mechanismscal cerebral ischemia/reperfusion. Neurosci Lett 2014; 573:16., Vadasz I, Lecuona E, et al. High CO2 levels impair alveolar epithelialn independently of pH. PloS One 2007; 2:e1238.

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iphosphatase function. Chest 1999; 116 (Suppl 1):29S30S.

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lth

33. Vadasz I, Dada LA, Briva A, et al. AMP-activated protein kinase regulatesCO2-induced alveolar epithelial dysfunction in rats and human cells bypromoting Na,K-ATPase endocytosis. J Clin Invest 2008; 118:752762.

34. Welch LC, Lecuona E, Briva A, et al. Extracellular signal-regulated kinase(ERK) participates in the hypercapnia-induced Na,K-ATPase downregulation.FEBS Lett 2010; 584:39853989.

35. Cummins EP, Oliver KM, Lenihan CR, et al. NF-kappaB links CO2 sensing toinnate immunity and inflammation in mammalian cells. J Immunol 2010;185:44394445.

36. Oliver KM, Lenihan CR, Bruning U, et al. Hypercapnia induces cleavage andnuclear localization of RelB protein, giving insight into CO2 sensing andsignaling. J Biol Chem 2012; 287:1400414011.

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38.&&

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These two papers [37,38&&], when taken together, not only show the importance of thecarbon dioxide molecule itself but also the importance of HCO3

in the regulation ofcellular signaling pathways during HCA. If pools of cAMP are sensitive to bicarbonatelevels above normal and increased cAMP leads to the endocytosis of the Na,K-ATPasetransporter, this has significant clinical impact when attempts are made to buffer the lowpH seen with increased arterial blood partial pressure of carbon dioxide.

39. Otulakowski G, Engelberts D, Gusarova GA, et al. Hypercapnia attenuatesventilator induced lung injury via a disintegrin and metalloprotease-17.J Physiol 2014; 592 (Pt 20):45074521.

40. Wang N, Gates KL, Trejo H, et al. Elevated CO2 selectively inhibits interleukin-6 and tumor necrosis factor expression and decreases phagocytosis in themacrophage. FASEB J 2010; 24:21782190.

41. Cohen TS, Gray Lawrence G, Khasgiwala A, Margulies SS. MAPK activationmodulates permeability of isolated rat alveolar epithelial cell monolayersfollowing cyclic stretch. PloS One 2010; 5:e10385.

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43. Shiomi T, Tschumperlin DJ, Park JA, et al. TNF-alpha-converting enzyme/adisintegrin and metalloprotease-17 mediates mechanotransduction in mur-ine tracheal epithelial cells. Am J Respir Cell Mol Biol 2011; 45:376385.

44. Fathi AR, Yang C, Bakhtian KD, et al. Carbon dioxide influence on nitric oxideproduction in endothelial cells and astrocytes: cellular mechanisms. Brain Res2011; 1386:5057.

45. Schwartges I, Picker O, Beck C, et al. Hypercapnic acidosis preserves gastricmucosal microvascular oxygen saturation in a canine model of hemorrhage.Shock 2010; 34:636642.

46. Akca O, Kurz A, Fleischmann E, et al. Hypercapnia and surgical site infection:a randomized trial. Brit J Anaesth 2013; 111:759767.

Respiratory system

12 Copyright 2015 Wolters Kluwer Heawww.co-criticalcare.com, Inc. All rights reserved.Volume 21 Number 1 February 2015