Severe Acute Injury Research Articles

Pentraxin 3 in acute respiratory distress syndrome: An early marker of severity*

Pentraxin 3 is a fluid phase receptor involved in innate immunity. It belongs to the Pentraxins family, as C-reactive protein does. Pentraxin 3 is produced by a variety of tissue cells, whereas only the liver produces C-reactive protein. Pentraxin 3 plays a unique role in the regulation of inflammation. Acute lung injury and acute respiratory distress syndrome are characterized by an important inflammatory reaction. We investigated the role of pentraxin 3 as a marker of severity and outcome predictor of acute lung injury and acute respiratory distress syndrome. We measured circulating pentraxin 3 and C-reactive protein levels within 24 hrs from intubation (day 1), after 24 hrs from the first sample, then every 3 days for the first month and then once a week, until discharge from the intensive care unit. Pentraxin 3 was also measured in bronchoalveolar lavages, performed when clinically indicated. One university medical center general intensive care unit. The study included 21 patients affected by acute lung injury and acute respiratory distress syndrome (1994 Consensus Conference criteria). None. Pentraxin 3 plasma levels were high with a peak on the first day (median 71.05 ng/mL, interquartile range 52.37-117.38 ng/mL, normal values <2 ng/mL), declining thereafter. C-reactive protein peaked later and remained at relatively high values. Out of several day 1 parameters, pentraxin 3 was the only significant difference between survivors and nonsurvivors. Pentraxin 3 levels were positively correlated with lung injury score values (p < 0.001) and number of organ failures (p < 0.001). Pentraxin 3 was present in bronchoalveolar lavages fluids (5.03 ng/mL, interquartile range 1.52-8.48 ng/mL) and bronchoalveolar lavages positive to bacterial culture were associated with significantly higher pentraxin 3 values (p < 0.05). The results presented here show that pentraxin 3 is elevated in acute lung injury and acute respiratory distress syndrome and that its levels correlate with parameters of lung injury and systemic involvement. The clinical and pathophysiological significance of pentraxin 3 in acute lung injury and acute respiratory distress syndrome deserves further scrutiny.

Oxidation of Plasma Cysteine/Cystine Redox State in Endotoxin-Induced Lung Injury

Several lines of evidence indicate that perturbations in the extracellular thiol/disulfide redox environment correlate with the progression and severity of acute lung injury (ALI). Cysteine (Cys) and its disulfide Cystine (CySS) constitute the most abundant, low-molecular-weight thiol/disulfide redox couple in the plasma, and Cys homeostasis is adversely affected during the inflammatory response to infection and injury. While much emphasis has been placed on glutathione (GSH) and glutathione disulfide (GSSG), little is known about the regulation of the Cys/CySS couple in ALI. The purpose of the present study was to determine whether endotoxin administration causes a decrease in Cys and/or an oxidation of the plasma Cys/CySS redox state (E(h) Cys/CySS), and to determine whether these changes were associated with changes in plasma E(h) GSH/GSSG. Mice received endotoxin intraperitoneally, and GSH and Cys redox states were measured at time points known to correlate with the progression of endotoxin-induced lung injury. E(h) in mV was calculated using Cys, CySS, GSH, and GSSG values by high-performance liquid chromatography and the Nernst equation. We observed distinct effects of endotoxin on the GSH and Cys redox systems during the acute phase; plasma E(h) Cys/CySS was selectively oxidized early in response to endotoxin, while E(h) GSH/GSSG remained unchanged. Unexpectedly, subsequent oxidation of E(h) GSH/GSSG and E(h) Cys/CySS occurred as a consequence of endotoxin-induced anorexia. Taken together, the results indicate that enhanced oxidation of Cys, altered transport of Cys and CySS, and decreased food intake each contribute to the oxidation of plasma Cys/CySS redox state in endotoxemia.

Activation of AMPK attenuates neutrophil proinflammatory activity and decreases the severity of acute lung injury

AMP-activated protein kinase (AMPK) is activated by increases in the intracellular AMP-to-ATP ratio and plays a central role in cellular responses to metabolic stress. Although activation of AMPK has been shown to have anti-inflammatory effects, there is little information concerning the role that AMPK may play in modulating neutrophil function and neutrophil-dependent inflammatory events, such as acute lung injury. To examine these issues, we determined the effects of pharmacological activators of AMPK, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside (AICAR) and barberine, on Toll-like receptor 4 (TLR4)-induced neutrophil activation. AICAR and barberine dose-dependently activated AMPK in murine bone marrow neutrophils. Exposure of LPS-stimulated neutrophils to AICAR or barberine inhibited release of TNF-alpha and IL-6, as well as degradation of IkappaBalpha and nuclear translocation of NF-kappaB, compared with findings in neutrophil cultures that contained LPS without AICAR or barberine. Administration of AICAR to mice resulted in activation of AMPK in the lungs and was associated with decreased severity of LPS-induced lung injury, as determined by diminished neutrophil accumulation in the lungs, reduced interstitial pulmonary edema, and diminished levels of TNF-alpha and IL-6 in bronchoalveolar lavage fluid. These results suggest that AMPK activation reduces TLR4-induced neutrophil activation and diminishes the severity of neutrophil-driven proinflammatory processes, including acute lung injury.

Plasma receptor for advanced glycation end products and clinical outcomes in acute lung injury

Objectives:To determine whether baseline plasma levels of the receptor for advanced glycation end products (RAGE), a novel marker of alveolar type I cell injury, are associated with the severity and...

Angiopoietin-2, permeability oedema, occurrence and severity of ALI/ARDS in septic and non-septic critically ill patients

Background:Angiopoietin-2 and vascular endothelial growth factor (VEGF) may impair vascular barrier function while angiopoietin-1 may protect it. It was hypothesised that circulating angiopoietin-2 is associated with pulmonary permeability oedema and...

Statin Therapy within the Perioperative Period

STATINS are highly effective in lowering serum cholesterol concentrations through 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibition and thus are central to the primary and secondary prevention of cardiovascular disease. More than 50% of patients undergoing major vascular surgery and 80% undergoing cardiac surgery are on chronic statin therapy. 1,2 Statins also exert numerous lipid-independent or “pleiotropic” effects (effects that were not expected during drug development) as a result of their ability to inhibit the inflammatory response, reduce thrombosis, enhance fibrinolysis, decrease platelet reactivity, inhibit cell growth, reduce ischemia–reperfusion injury, and restore endothelial function. These beneficial effects result predominantly from the modulation of the complex interplay between the pathologic triad of inflammation, dynamic obstruction, and thrombosis. 3 This triad is integral to the surgical stress response and central to postoperative outcomes. However, recent reports noted that patients who undergo postoperative statin withdrawal experience increased cardiac morbidity when compared with patients who undergo early postoperative readministration of statins or with patients not treated with statins. 1,4 These facts raise several important questions for the anesthesiologist regarding statin therapy during the perioperative period: (1) Do statins modify perioperative risk? (2) Is continuation or discontinuation of statin therapy during the perioperative period associated with additional risk? (3) Do the potential benefits of statin therapy outweigh the potential risks? This review of the literature explores the risks and benefits associated with perioperative statin therapy.

Impact of Age on Long-Term Recovery From Traumatic Brain Injury

Marquez de la Plata CD, Hart T, Hammond FM, Frol AB, Hudak A, Harper CR, O'Neil-Pirozzi TM, Whyte J, Carlile M, Diaz-Arrastia R. Impact of age on long-term recovery from traumatic brain injury. Objective To determine whether older persons are at increased risk for progressive functional decline after traumatic brain injury (TBI). Design Longitudinal cohort study. Setting Traumatic Brain Injury Model Systems (TBIMS) rehabilitation centers. Participants Subjects enrolled in the TBIMS national dataset. Interventions Not applicable. Main Outcome Measures Disability Rating Scale (DRS), FIM instrument cognitive items, and the Glasgow Outcome Scale–Extended. Results Participants were separated into 3 age tertiles: youngest (16–26y), intermediate (27–39y), and oldest (≥40y). DRS scores were comparable across age groups at admission to a rehabilitation center. The oldest group was slightly more disabled at discharge from rehabilitation despite having less severe acute injury severity than the younger groups. Although DRS scores for the 2 younger groups improved significantly from year 1 to year 5, the greatest magnitude of improvement in disability was seen among the youngest group. In addition, after dividing patients into groups according to whether their DRS scores improved (13%), declined (10%), or remained stable (77%) over time, the likelihood of decline was found to be greater for the 2 older groups than for the youngest group. A multiple regression model showed that age has a significant negative influence on DRS score 5 years post-TBI after accounting for the effects of covariates. Conclusions This study supported our primary hypothesis that older patients show greater decline over the first 5 years after TBI than younger patients. In addition, the greatest amount of improvement in disability was observed among the youngest group of survivors. These results suggest that TBI survivors, especially older patients, may be candidates for neuroprotective therapies after TBI.

TREATMENT WITH H2S-RELEASING DICLOFENAC PROTECTS MICE AGAINST ACUTE PANCREATITIS-ASSOCIATED LUNG INJURY

Impaired lung function in severe acute pancreatitis is the primary cause of morbidity and mortality in this condition. Hydrogen sulfide (H(2)S) is a naturally occurring gas that has been shown to be a potent vasodilator. Diclofenac is a nonsteroidal anti-inflammatory drug and has been shown to have anti-inflammatory, analgesic, and antipyretic activity. ACS15 is an H(2)S-releasing derivative of diclofenac. Little is known about its effectiveness as an anti-inflammatory drug. In this report, we describe the effect of diclofenac and its H(2)S-releasing derivative on acute pancreatitis and associated lung injury in the mouse. Acute pancreatitis was induced in mice by hourly i.p. injections of cerulein. Diclofenac and ACS15 were administered either 1 hour before or 1 hour after starting cerulein injections, and the severity of acute pancreatitis and associated lung injury was assessed. The severity of acute pancreatitis was determined by hyperamylasemia, neutrophil sequestration in the pancreas (pancreatic myeloperoxidase activity), and pancreatic acinar cell injury/necrosis on histological examination of pancreas sections. The severity of acute pancreatitis-associated lung injury was assessed by neutrophil sequestration in the lungs (lung myeloperoxidase activity) and by histological examination of lung sections. ACS15, given prophylactically and therapeutically, significantly reduced lung inflammation without having any significant effect on pancreatic injury. These results suggest the usefulness of H(2)S-releasing nonsteroidal anti-inflammatory drugs as potential treatments for pancreatitis-associated lung injury.

Increased tissue factor expression in the lung reflects the severity of acute lug injury

Increased tissue factor expression in the lung reflects the severity of acute lug injury

Carbon Monoxide Can Prevent Acute Lung Injury Observed After Ischemia Reperfusion of the Lower Extremities

Pulmonary expression of heme oxygenase has been observed in multiple studies. This expression has been found beneficial in decreasing the severity of acute lung injury (ALI) post ischemia-reperfusion (I/R). The aim of this study was to assess the role of exogenous administration of the end-products of heme oxygenase reaction, carbon monoxide, and bilirubin, in the severity of ALI. We compared five groups of rats (n = 7/group) including a sham group and four I/R of the lower extremities by clamping the abdominal aorta for 2 h followed by reperfusion for 2 h. The four I/R groups included a control group, one pretreated with bilirubin (50 micromol/kg IV), another with inhaled carbon monoxide (CO) (250 ppm), and the last pretreated with both. The severity of ALI has been evaluated by a histological assay grading neutrophilic infiltration, as well as a study of the microvascular permeability using the Evans blue. The administration of CO prevented pulmonary microvascular permeability alteration noted after I/R of the lower limbs (pulmonary content of Evans blue: 141 +/- 23 microg/g of tissue in the isolated I/R group versus 68 +/- 34 microg/g of tissue in CO group; P < 0.001). Histologically CO administration inhibited neutrophilic sequestration observed after I/R. On the other hand, treatment by bilirubin alone (50 micromol/kg IV) did not modify the extent of pulmonary injury. Exogenous administration of carbon monoxide by inhalation at low doses prevented ALI post-I/R in this model.

Intrapulmonary Delivery of Bone Marrow-Derived Mesenchymal Stem Cells Improves Survival and Attenuates Endotoxin-Induced Acute Lung Injury in Mice

Recent in vivo and in vitro work suggests that mesenchymal stem cells (MSC) have anti-inflammatory properties. In this study, we tested the effect of administering MSC directly into the airspaces of the lung 4 h after the intrapulmonary administration of Escherichia coli endotoxin (5 mg/kg). MSC increased survival compared with PBS-treated control mice at 48 h (80 vs 42%; p < 0.01). There was also a significant decrease in excess lung water, a measure of pulmonary edema (145 +/- 50 vs 87 +/- 20 microl; p < 0.01), and bronchoalveolar lavage protein, a measure of endothelial and alveolar epithelial permeability (3.1 +/- 0.4 vs 2.2 +/- 0.8 mg/ml; p < 0.01), in the MSC-treated mice. These protective effects were not replicated by the use of further controls including fibroblasts and apoptotic MSC. The beneficial effect of MSC was independent of the ability of the cells to engraft in the lung and was not related to clearance of the endotoxin by the MSC. MSC administration mediated a down-regulation of proinflammatory responses to endotoxin (reducing TNF-alpha and MIP-2 in the bronchoalveolar lavage and plasma) while increasing the anti-inflammatory cytokine IL-10. In vitro coculture studies of MSC with alveolar macrophages provided evidence that the anti-inflammatory effect was paracrine and was not cell contact dependent. In conclusion, treatment with intrapulmonary MSC markedly decreases the severity of endotoxin-induced acute lung injury and improves survival in mice.

Interleukin‐17 as a new marker of severity of acute hepatic injury

To determine cytokines associated with the progression of acute hepatic injury (AHI), we comprehensively evaluated the serum levels of 17 cytokines. We simultaneously measured serum levels of 17 cytokines on admission using a newly developed suspension array protein assay system in 51 patients with AHI, including 15 conventional AHI (CAHI), 15 severe AHI (SAHI) and 21 fulminant hepatic failure (FHF). Interleukin (IL)-6, IL-8 and IL-17 levels were significantly different among the three disease types as determined by one-way analysis of variance, and only the IL-17 level showed a significant elevation in SAHI and FHF than in CAHI. Namely, the IL-17 levels in SAHI and FHF patients were 4.4 (2.0-11.0) (mean [1 .s.d. range]) and 5.6 (2.0-18.5) pg/mL, respectively, whereas all CAHI patients showed levels lower than the lower limit of detection (2.0 pg/mL). In multiple regression analysis for each factor of model for end-stage liver disease (MELD) score, only IL-10 level was selected as the significant independent variable for total bilirubin level, only IL-17 level for prothrombin time, and TNF-alpha and IL-1beta levels for creatinine level. These data suggest the usefulness of serum IL-17 level in evaluating the severity of AHI, thus emphasizing the necessity for the basic investigation of the pathological role of IL-17 in acute hepatitis.

The response to recruitment worsens with progression of lung injury and fibrin accumulation in a mouse model of acid aspiration

Reopening the injured lung with deep inflation (DI) and positive end-expiratory pressure (PEEP) likely depends on the duration and severity of acute lung injury (ALI), key features of which include increased alveolar permeability and fibrin accumulation. We hypothesized that the response to DI and PEEP would worsen as ALI evolves and that this would correspond with increasing accumulation of alveolar fibrin. C57BL/6 mice were anesthetized and aspirated 75 microl of HCl (pH 1.8) or buffered normal saline. Subgroups were reanesthetized 4, 14, 24, and 48 h later. Following DI, tissue damping (G) and elastance (H) were measured periodically at PEEP of 1, 3, and 6 cmH(2)O, and air within the lung (thoracic gas volume) was quantified by microcomputed tomography. Following DI, G and H increased with time during progressive lung derecruitment, the latter confirmed by microcomputed tomography. The rise in H was greater in acid-injured mice than in controls (P < 0.05) and also increased from 4 to 48 h after acid aspiration, reflecting progressively worsening injury. The rise in H was reduced by PEEP, but this effect was significantly blunted by 48 h (P < 0.05), also confirmed by thoracic gas volume. Lung permeability and alveolar fibrin also increased over the 48-h study period, accompanied by increasing levels and transcription of the fibrinolysis inhibitor plasminogen activator inhibitor-1. Lung injury worsens progressively in mice during the 48 h following acid aspiration. This injury manifests as progressively increasing alveolar instability, likely due to surfactant dysfunction caused by increasing levels of alveolar protein and fibrin.

Modulating cofactors of acute lung injury 2005–2006: any closer to ‘prime time’?

Considerable progress has recently been made in understanding the modulation of acute lung injury by cofactors that are not traditionally considered 'pulmonary' in nature. We will review findings regarding some of these extrapulmonary cofactors, focusing on those most readily manipulated in the current clinical setting. Recent studies have demonstrated that limiting fluid administration in the setting of acute lung injury might improve surrogate outcomes; that hypercapnea and induced hypothermia might protect against or attenuate acute lung injury; that corticosteroids can improve mechanics but not mortality in acute respiratory distress syndrome; a potential role for concomitant administration of colloid and diuretic in acute lung injury; and the potential benefits of inhaled beta agonists in acute lung injury. There are a number of simple, low-cost, and rapidly deployable approaches to reducing the severity of acute lung injury that are not directly pulmonary in origin. These interventions could be rapidly implemented in any intensive care unit, once evidence for their efficacy and safety is adequate.

ZINC SUPPLEMENTATION IMPROVES ALVEOLAR EPITHELIAL BARRIER FUNCTION IN THE ALCOHOLIC RAT LUNG.

Alcohol abuse independently increases the risk of developing the acute respiratory distress syndrome (ARDS) two- to fourfold in critically ill patients with sepsis, trauma, or massive gastric aspiration. We have shown in experimental animal models that chronic alcohol ingestion causes oxidative stress within the alveolar space, impairs alveolar epithelial barrier integrity, and increases sepsis-mediated acute lung injury. However, the precise mechanisms by which alcohol abuse renders the lung susceptible to injury are still under investigation. Alcoholics are known to be deficient in the essential micronutrient zinc (Zn), which is critical for diverse cellular functions within the respiratory tract, including stabilization of membranes and tissue repair. Therefore, we hypothesized that Zn deficiency in the alveolar space may contribute significantly to the cellular dysfunction and increased epithelial permeability in the “alcoholic lung” and that these defects could be corrected by Zn supplementation. Male Sprague-Dawley rats were fed the Lieber-DeCarli liquid diet ± alcohol for 6 weeks. Zn acetate (0.2%) was added to the alcohol diets of some rats. Alveolar epithelial cells were isolated from each rat and grown to monolayer confluence (8 days), at which time the permeability was determined by measuring the flux of radiolabeled sucrose across each monolayer. In some experiments, Zn acetate (1-20 μM) was added to the alveolar epithelial cell monolayers in vitro to determine whether Zn had any direct effects on the alcoholic airway epithelium. Chronic alcohol ingestion significantly increased the alveolar epithelial permeability compared with control-fed rats. Zinc supplements, either in vivo or in vitro, significantly decreased the alcohol-induced abnormal permeability in the alveolar epithelium, and in the in vitro experiments, this protective effect of Zn was concentration dependent. Interestingly, Zn treatment, either in vivo or in vitro, appeared to increase the expression of the tight junction proteins occludin and ZO-1 as assessed by fluorescence microscopy. These results suggest that Zn deficiency, in part through changes in tight junction assembly and/or function, may be one of the mechanisms by which alcohol abuse impairs alveolar epithelial barrier integrity and increases the susceptibility to acute lung injury. We speculate that Zn supplementation could improve alveolar epithelial barrier function and decrease the incidence and/or severity of acute lung injury in this highly vulnerable patient population.

Evaluation of Parameters of Serially Monitored F-wave in Acute Cervical Spinal Cord Injury

In this study, we aimed to determine how physicians can evaluate the severity of acute traumatic spinal cord injury (SCI) and predict the prognosis of this injury using the relationships of changes in clinical features and electrophysiological examination results. Serial recordings of F-waves were performed on 20 consecutive cervical SCI patients. In 12 of the patients, changes in several parameters of F-waves which were elicited by median and ulnar nerve stimulations were examined by analyzing their relationships to clinical symptoms. The maximum amplitude of the F-waves (F-max) elicited by median nerve stimulation was found to be the most reliable (statistically significant) parameter for distinguishing clinically improved patients from nonimproved patients for the prognosis in the early stages after trauma. Other parameters, including the incidence of F-waves and the mean F-wave amplitude both of which were elicited by median nerve stimulation, were somewhat helpful for predicting the prognosis. These parameters of F-waves evoked by ulnar nerve stimulation could be useful for several weeks post-trauma.

Involvement of the Urokinase Kringle Domain in Lipopolysaccharide-Induced Acute Lung Injury

Urokinase plasminogen activator (uPA) plays a major role in fibrinolytic processes and also can potentiate LPS-induced neutrophil activation through interactions with its kringle domain (KD). To investigate the role of the uPA KD in modulating acute inflammatory processes in vivo, we cloned and then developed Abs to the murine uPA KD. Increased pulmonary expression of uPA and the uPA KD was present in the lungs after LPS exposure. Administration of anti-kringle Abs diminished LPS-induced up-regulation of uPA and uPA KD in the lungs, and also decreased the severity of LPS-induced acute lung injury, as determined by development of lung edema, pulmonary neutrophil accumulation, histology, and lung IL-6, MIP-2, and TNF-alpha cytokine levels. These proinflammatory effects of the uPA KD appeared to be mediated through activation of Akt and NF-kappaB. The present studies indicate that the uPA KD plays a major role in the development of TLR4-mediated acute inflammatory processes, including lung injury. Blockade of the uPA KD may prevent the development or ameliorate the severity of acute lung injury induced through TLR4-dependent mechanisms, such as would occur in the setting of Gram-negative pulmonary or systemic infection.

Day-of-Injury Computerized Tomography, Rehabilitation Status, and Development of Cerebral Atrophy in Persons with Traumatic Brain Injury

To compare day-of-injury (DOI) computerized tomography (CT) findings with acute injury severity markers, disability at acute hospital admission and discharge from inpatient rehabilitation, injury severity markers, and degree of postacute cerebral atrophy on magnetic resonance imaging (MRI). Retrospective chart review of 240 consecutive traumatic brain injury (TBI) admissions (mean age 31.7 +/- 15.8 yrs) with moderate-to-severe initial brain injury. All DOI CT abnormalities were qualitatively rated. Disability was assessed using the Disability Rating Scale (DRS) and the FIM measure. In a representative subset, cerebral atrophy was determined by the ventricle-to-brain ratio (VBR) method and quantified from MRI scans 25 or more days postinjury. CT classification resulted in nonsignificant differences in DRS and FIM ratings at the time of discharge from the rehabilitation unit, except in brainstem injury subjects who had significantly higher DRS and lower FIM scores at rehabilitation discharge. At 25 or more days postinjury, presence of any DOI CT abnormality was associated with larger VBR. Increased VBR, as an index of cerebral atrophy, was associated with worse rehabilitation discharge DRS and FIM ratings. Other than brainstem injury, DOI CT findings relate poorly to rehabilitation outcome. Presence of DOI CT abnormalities were associated with the development of cerebral atrophy, which was associated with poorer rehabilitation discharge DRS and FIM scores.

The emergency nursing for patients with acute severe chest injury

The emergency nursing for patients with acute severe chest injury

Effects of HSP70.1/3 gene knockout on NF-κB-mediated and cytokine-induced reduction in alveolar ion and fluid transport

LETTERS TO THE EDITOREffects of HSP70.1/3 gene knockout on NF-κB-mediated and cytokine-induced reduction in alveolar ion and fluid transportMichael EisenhutMichael EisenhutPublished Online:01 Jan 2007https://doi.org/10.1152/ajplung.00278.2006This is the final version - click for previous versionMoreSectionsPDF (29 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInEmailWeChat to the editor: Singleton and Wischmeyer (8) reported on the effects of HSP70.1/3 gene knockout on acute respiratory distress syndrome in a mouse model of septicemia. They found that the absence of the heat shock protein HSP70 was associated with an activation of NF-κB, increased levels of TNF, and more extensive alveolar exudate. A recent study by another group (4) using a mouse model of endotoxin-induced acute lung injury confirmed the importance of NF-κB activation in induction of lung injury by demonstrating a complete prevention of lung edema by a specific IκB kinase inhibitor. The authors (4, 8) have not expanded on the mechanisms leading to more extensive pulmonary fluid accumulation under conditions of NF-κB activation, which may be important for the understanding of the pathophysiology of septicemia-induced pulmonary edema and open avenues for therapeutic interventions. NF-κB is a potent inducer of the production of TNF and IL-1 (6). Both these cytokines reduce alveolar epithelial sodium and chloride and the associated fluid transport and can hence contribute to pulmonary edema accumulation (2). In meningococcal septicemia, pulmonary edema has been associated with reduced systemic epithelial sodium and chloride transport (3). The mechanisms have been investigated, and TNF was found to reduce epithelial sodium channel (ENaC) expression in alveolar type II cells (1). IL-1 was noted to reduce cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel function and ENaC expression in the same cell population (2). Nitric oxide induced by these cytokines may also be involved since it has been found to reduce alveolar ENaC and sodium potassium ATPase function (5).Research into therapeutic interventions to reduce the effects of NF-κB activation should focus on its effects on epithelial ion transport. Alveolar epithelial ion transport can be influenced by drugs like β-agonists, which increase intracellular cAMP levels activating CFTR (2). This may be the reason why β-agonists have been found to reduce lung water in patients with acute lung injury (7). A reduction of NF-κB function itself, which has an important role in hematopoiesis and for the differentiation and maturation of both myeloid and lymphoid immune cells (6), could have significant adverse effects.REFERENCES1 Dagenais A, Frechette R, Yamagata T, Yamagata T, Carmel JF, Clermont ME, Brochiero E, Masse C, Berthiaume T. Downregulation of ENaC activity and expression by TNF-α in alveolar epithelial cells. Am J Physiol Lung Cell Mol Physiol 286: L301–L311, 2004.Link | ISI | Google Scholar2 Eisenhut M. Changes in ion transport in inflammatory disease. J Inflamm 3: 5, 2006.Crossref | Google Scholar3 Eisenhut M, Wallace H, Barton P, Gaillard E, Newland P, Diver M, Southern KW. Pulmonary edema in meningococcal septicemia associated with reduced epithelial chloride transport. Pediatr Crit Care Med 7: 119–124, 2006.Crossref | PubMed | ISI | Google Scholar4 Everhart MB, Han W, Sherrill TP, Arutiunov Polosukhin VV, Burke JR, Sadikot RT, Christman JW, Yull FE, Blackwell TS. Duration and intensity of NF-κB activity determine the severity of endotoxin-induced acute lung injury. J Immunol 176: 4995–5005, 2006.Crossref | PubMed | ISI | Google Scholar5 Guo Y, DuVall MD, Crow JP, Matalon S. Nitric oxide inhibits Na+ absorption across cultured alveolar type II monolayers. Am J Physiol Lung Cell Mol Physiol 274: L369–L377, 1998.Link | ISI | Google Scholar6 Liu SF, Malik AB. NF-κB activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol 290: L622–L645, 2006.Link | ISI | Google Scholar7 Perkins GD, McAuley DF, Thickett DR, Gao F. The beta-agonist lung injury trial (BALTI): a randomized placebo-controlled clinical trial. Am J Respir Crit Care Med 173: 281–287, 2006.Crossref | PubMed | ISI | Google Scholar8 Singleton KD, Wischmeyer PE. Effects of HSP70.1/3 gene knockout on acute respiratory distress syndrome and the inflammatory response following sepsis. Am J Physiol Lung Cell Mol Physiol 290: L956–L961, 2006.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: M. Eisenhut, 5 Prestwood Crescent, Liverpool L14 2ED, United Kingdom (e-mail: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByReply to EisenhutKristen D. Singleton, and Paul E. Wischmeyer1 January 2007 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 292, No. 1 More from this issue > Volume 292Issue 1January 2007Pages L365-L365 Copyright & PermissionsCopyright © 2007 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00278.2006PubMed16963529History Published online 1 January 2007 Published in print 1 January 2007 Metrics