Many mechanically ventilated patients with acute respiratory distress syndrome (ARDS) develop pulmonary fibrosis. Stresses induced by mechanical ventilation may explain the development of fibrosis by a number of mechanisms (e.g. damage the alveolar epithelium, biotrauma).
To test the hypothesis that mechanical ventilation plays an important role in the pathogenesis of lung fibrosis.
C57BL/6 mice were randomized into four groups: healthy controls; hydrochloric acid (HCl) aspiration alone; vehicle control solution followed 24 h later by mechanical ventilation (peak inspiratory pressure 22 cmH2O and PEEP 2 cmH2O for 2h); and acid aspiration followed 24h later by mechanical ventilation. The animals were monitored for up to 15 days after acid aspiration. To explore the direct effects of mechanical stress on lung fibrotic formation, human lung epithelial cells (BEAS-2B) were exposed to mechanical stretch for up to 48 h.
Measurement and Main Results
Impaired lung mechanics after mechanical ventilation was associated with increased lung hydroxyproline content, and increased expression of transforming growth factor-β (TGF-β), β-catenin and mesenchymal markers (α-SMA and Vimentin) at both the gene and protein levels. Expression of epithelial markers including cytokeratin-8, E-cadherin and pro-surfactant protein B decreased. Lung histology demonstrated fibrosis formation and potential epithelial-mesenchymal transition (EMT). In vitro direct mechanical stretch of BEAS-2B cells resulted in similar fibrotic and EMT formation.
Mechanical stress induces lung fibrosis, and EMT may play an important role in mediating the ventilator-induced lung fibrosis.
PMID: 21926573 CAMSID: cams2914
Acute lung injury; ventilator-induced lung injury; extracellular matrix
A recent individual patient data (IPD) meta-analysis suggested that patients with moderate or severe acute respiratory distress syndrome (ARDS) benefit from higher positive end-expiratory pressure (PEEP) ventilation strategies. However, thresholds for continuous variables (eg, hypoxaemia) are often arbitrary and linearity assumptions in regression approaches may not hold; the multivariable fractional polynomial interaction (MFPI) approach can address both problems. The objective of this study was to apply the MFPI approach to investigate interactions between four continuous patient baseline variables and higher versus lower PEEP on clinical outcomes.
Pooled data from three randomised trials in intensive care identified by a systematic review.
2299 patients with acute lung injury requiring mechanical ventilation.
Higher (N=1136) versus lower PEEP (N=1163) ventilation strategy.
Prespecified outcomes included mortality, time to death and time-to-unassisted breathing. We examined the following continuous baseline characteristics as potential effect modifiers using MFPI: PaO2/FiO2 (arterial partial oxygen pressure/ fraction of inspired oxygen), oxygenation index, respiratory system compliance (tidal volume/(inspiratory plateau pressure−PEEP)) and body mass index (BMI).
We found that for patients with PaO2/FiO2 below 150 mm Hg, but above 100 mm Hg or an oxygenation index above 12 (moderate ARDS), higher PEEP reduces hospital mortality, but the beneficial effect appears to level off for patients with very severe ARDS. Patients with mild ARDS (PaO2/FiO2 above 200 mm Hg or an oxygenation index below 10) do not seem to benefit from higher PEEP and might even be harmed. For patients with a respiratory system compliance above 40 mL/cm H2O or patients with a BMI above 35 kg/m2, we found a trend towards reduced mortality with higher PEEP, but there is very weak statistical confidence in these findings.
MFPI analyses suggest a nonlinear effect modification of higher PEEP ventilation by PaO2/FiO2 and oxygenation index with reduced mortality for some patients suffering from moderate ARDS.
Study registration number
ARDS; acute lung injury; treatment interaction; multivariable fractional polynomials; IPD meta-analysis
One of the most challenging problems in critical care medicine is the management of patients with the acute respiratory distress syndrome. Increasing evidence from experimental and clinical studies suggests that mechanical ventilation, which is necessary for life support in patients with acute respiratory distress syndrome, can cause lung fibrosis, which may significantly contribute to morbidity and mortality. The role of mechanical stress as an inciting factor for lung fibrosis versus its role in lung homeostasis and the restoration of normal pulmonary parenchymal architecture is poorly understood. In this review, the authors explore recent advances in the field of pulmonary fibrosis in the context of acute respiratory distress syndrome, concentrating on its relevance to the practice of mechanical ventilation, as commonly applied by anesthetists and intensivists. The authors focus the discussion on the thesis that mechanical ventilation—or more specifically, that ventilator-induced lung injury—may be a major contributor to lung fibrosis. The authors critically appraise possible mechanisms underlying the mechanical stress–induced lung fibrosis and highlight potential therapeutic strategies to mitigate this fibrosis.
PMID: 24732023 CAMSID: cams5673
Bacterial colonization of epithelial surfaces and subsequent transmigration across the mucosal barrier are essential for the development of infection. We hypothesized that the methyl-accepting proteins (MCPs), known as chemoreceptors expressed on Escherichia coli (E. coli) bacterial surface, play an important role in mediating bacterial transmigration. We demonstrated a direct interaction between human interleukin-8 (IL-8) and Tsr receptor, a major MCP chemoreceptor. Stimulation of human lung epithelial cell monolayer with IL-8 resulted in increased E. coli adhesion and transmigration of the native strain (RP437) and a strain expressing only Tsr (UU2373), as compared to a strain (UU2599) with Tsr truncation. The augmented E. coli adhesion and migration was associated with a higher expression of carcinoembryonic antigen-related cell adhesion molecule 6 and production of inflammatory cytokines/chemokines, and a lower expression of the tight junction protein claudin-1 and the plasma membrane protein caveolin-1 in lung epithelial cells. An increased E. coli colonization and pulmonary cytokine production induced by the RP437 and UU2373 strains was attenuated in mice challenged with the UU2599 strain. Our results suggest a critical role of the E. coli Tsr chemoreceptor in mediating bacterial colonization and transmigration across human lung epithelium during development of pulmonary infections.
Neutrophils are involved in the inflammatory responses during atherosclerosis. Human neutrophil peptides (HNPs) released from activated neutrophils exert immune modulating properties. We hypothesized that HNPs play an important role in neutrophil-mediated inflammatory cardiovascular responses in atherosclerosis.
Methods and Results
We examined the role of HNPs in endothelial-leukocyte interaction, platelet activation, and foam cell formation in vitro and in vivo. We demonstrated that stimulation of human coronary artery endothelial cells with clinically relevant concentrations of HNPs resulted in monocyte adhesion and transmigration; induction of oxidative stress in human macrophages, which accelerates foam cell formation; and activation and aggregation of human platelets. The administration of superoxide dismutase or anti-CD36 antibody reduced foam cell formation and cholesterol efflux. Mice deficient in double genes of low-density lipoprotein receptor and low-density lipoprotein receptor–related protein (LRP), and mice deficient in a single gene of LRP8, the only LRP phenotype expressed in platelets, showed reduced leukocyte rolling and decreased platelet aggregation and thrombus formation in response to HNP stimulation.
HNPs exert proatherosclerotic properties that appear to be mediated through LRP8 signaling pathways, suggesting an important role for HNPs in the development of inflammatory cardiovascular diseases.
PMID: 21817096 CAMSID: cams2910
atherosclerosis; leukocytes; transgenic models
Gamma amino butyric acid (GABA) is the major inhibitory neurotransmitter through activation of GABA receptors. Volatile anesthetics activate type A (GABAA) receptors resulting in inhibition of synaptic transmission. Lung epithelial cells have been recently found to express GABAA receptors that exert anti-inflammatory properties. We hypothesized that the volatile anesthetic sevoflurane (SEVO) attenuates lung inflammation through activation of lung epithelial GABAA receptors.
Sprague-Dawley rats were anesthetized with SEVO or ketamine/xylazine (KX). Acute lung inflammation was induced by intratracheal instillation of endotoxin, followed by mechanical ventilation for 4 h at a tidal volume of 15 mL/kg without positive end-expiratory pressure (two-hit lung injury model). To examine the specific effects of GABA, healthy human bronchial epithelial cells (BEAS-2B) were challenged with endotoxin in the presence and absence of GABA with and without addition of the GABAA receptor antagonist picrotoxin.
Anesthesia with SEVO improved oxygenation and reduced pulmonary cytokine responses compared to KX. This phenomenon was associated with increased expression of the π subunit of GABAA receptors and glutamic acid decarboxylase (GAD). The endotoxin-induced cytokine release from BEAS-2B cells was attenuated by the treatment with GABA, which was reversed by the administration of picrotoxin.
Anesthesia with SEVO suppresses pulmonary inflammation thus protects the lung from the two-hit injury. The anti-inflammatory effect of SEVO is likely due to activation of pulmonary GABAA signaling pathways.
PMID: 22711173 CAMSID: cams2911
volatile anesthetics; mechanical ventilation; inflammation
Human neutrophil peptides (HNP) kill microorganisms but also modulate immune responses through upregulation of the chemokine IL-8 by activation of the nucleotide P2Y6 receptor. However, the intracellular signaling mechanisms remain yet to be determined. Human lung epithelial cells (A549) and monocytes (U937) were stimulated with HNP in the absence and presence of the specific kinase inhibitors for Src, ERK1/2, p38 MAPK, JNK and Akt. HNP induced a rapid phosphorylation of the kinases in both cell types associated with a dose-dependent, selective production of IL-8 among ten cytokines assayed. The HNP-induced IL-8 production was blocked by the Src tyrosine kinase inhibitor PP2, MEK1/2 inhibitor U0126 and the PI3K inhibitor LY294002, but not by the JNK inhibitor SP600125 in both cell types. Treatment with the p38 inhibitor SB203580 attenuated the HNP-induced IL-8 production only in monocytes. Blockade of Src kinase blunted HNP-induced phosphorylation of the ERK1/2 and Akt but not p38 in monocytes. In contrast, Src inhibition had no effect on phosphorylation of the other kinases in the lung epithelial cells. We conclude that the activation of ERK1/2 and PI3K/Akt pathways is required for HNP-induced IL-8 release which occurs in a Src-independent manner in lung epithelial cells, while is Src-dependent in monocytes.
PMID: 17786963 CAMSID: cams3636
Defensins; cytokine; MAP kinase
The traditional view of atherosclerosis has recently been expanded from a predominantly lipid retentive disease to a coupling of inflammatory mechanisms and dyslipidemia. Studies have suggested a novel role for polymorphonuclear neutrophil (PMN)-dominant inflammation in the development of atherosclerosis. Human neutrophil peptides (HNPs), also known as α-defensins, are secreted and released from PMN granules upon activation and are conventionally involved in microbial killing. Current evidence suggests an important immunomodulative role for these peptides. HNP levels are markedly increased in inflammatory diseases including sepsis and acute coronary syndromes. They have been found within the intima of human atherosclerotic arteries, and their deposition in the skin correlates with the severity of coronary artery diseases. HNPs form complexes with LDL in solution and increase LDL binding to the endothelial surface. HNPs have also been shown to contribute to endothelial dysfunction, lipid metabolism disorder, and the inhibition of fibrinolysis. Given the emerging relationship between PMN-dominant inflammation and atherosclerosis, HNPs may serve as a link between them and as a biological marker and potential therapeutic target in cardiovascular diseases including coronary artery diseases and acute coronary syndromes.
PMID: 18805897 CAMSID: cams3639
α-defensins; inflammation; cytokine
It is well established that mechanical ventilation can injure the lung, producing an entity known as ventilator-induced lung injury (VILI). There are various forms of VILI, including volutrauma (i.e., injury caused by overdistending the lung), atelectrauma (injury due to repeated opening/closing of lung units), and biotrauma (release of mediators that can induce lung injury or aggravate pre-existing injury, potentially leading to multiple organ failure). Experimental data in the pediatric context are in accord with the importance of VILI, and appear to show age-related susceptibility to VILI, although a conclusive link between use of large Vts and mortality has not been demonstrated in this population. The relevance of VILI in the pediatric intensive care unit population is thus unclear. Given the physiological and biological differences in the respiratory systems of infants, children, and adults, it is difficult to directly extrapolate clinical practice from adults to children. This Critical Care Perspective analyzes the relevance of VILI to the pediatric population, and addresses why pediatric patients might be less susceptible than adults to VILI.
PMID: 25003705 CAMSID: cams5667
mechanical ventilation; ventilator-induced lung injury; pediatrics; animal studies; human studies
The human neutrophil peptides (HNP) bind to vascular smooth muscle cells and regulate vascular tone. We hypothesized that HNP act on endothelial cells to modulate the expression of vasoactive byproducts. We observed a time- and dose-dependent increase in the expression of cyclooxygenase-2 (COX-2) by human umbilical vein endothelial cells (HUVEC) in response to HNP stimulation, while COX-1 levels remained unchanged. Despite an upregulated expression of COX-2, HNP did not significantly enhance the production of the COX-2-derived prostaglandins PGI2 and PGE2. HNP significantly induced the release of endothelin-1 (ET-1) as well as the formation of nitrotyrosine. The HNP-induced COX-2 and ET-1 production was attenuated by the treatment with the oxygen free radical scavenger N-acetyl-L-cysteine, and the inhibitors of p38 MAPK and NF-κB, respectively. We conclude that HNP may play an important role in the regulation of the course of cardiovascular diseases by activating endothelial cells to produce vasoactive byproducts.
PMID: 18441204 CAMSID: cams3637
Inflammation; immunity; leukocyte
Mechanical ventilation can induce organ injury associated with overwhelming inflammatory responses. Excessive activation of poly(adenosine diphosphate-ribose) polymerase enzyme following massive DNA damage may aggravate inflammatory responses. We thus hypothesized that the pharmacological inhibition of poly(adenosine diphosphate-ribose) polymerase by PJ-34 will attenuate ventilator-induced lung injury.
Anesthetized rats were subjected to intratracheal instillation of lipopolysaccharide at a dose of 6 mg/kg. The animals were then randomized to receive mechanical ventilation at either low tidal volume (6 mL/kg) with 5 cmH2O positive end-expiratory pressure or high tidal volume (15 mL/kg) with zero positive end-expiratory pressure, in the presence and absence of intravenous administration of PJ-34.
The high tidal volume ventilation resulted in an increase in poly (adenosine diphosphate-ribose) polymerase activity in the lung. The treatment with PJ-34 maintained a greater oxygenation and a lower airway plateau pressure than the vehicle control group. This was associated with a decreased level of interleukin-6, active plasminogen activator inhibitor-1 in the lung, attenuated leukocyte lung transmigration and reduced pulmonary edema and apoptosis. The administration of PJ-34 also decreased the systemic levels of tumor necrosis factor-α and interleukin-6, and attenuated the degree of apoptosis in the kidney.
The pharmacological inhibition of poly(adenosine diphosphate-ribose) polymerase reduces ventilator-induced lung injury and protects kidney function.
PMID: 18212571 CAMSID: cams3638
During conventional Neurally Adjusted Ventilatory Assist (NAVA), the electrical activity of the diaphragm (EAdi) is used for triggering and cycling-off inspiratory assist, with a fixed PEEP (so called “Triggered Neurally Adjusted Ventilatory Assist” or “tNAVA”). However, significant post-inspiratory activity of the diaphragm can occur, believed to play a role in maintaining end-expiratory lung volume. Adjusting pressure continuously, in proportion to both inspiratory and expiratory EAdi (Continuous NAVA, or cNAVA), would not only offer inspiratory assist for tidal breathing, but also may aid in delivering a “neurally adjusted PEEP”, and more specific breath-by-breath unloading.
Nine adult New Zealand white rabbits were ventilated during independent conditions of: resistive loading (RES1 or RES2), CO2 load (CO2) and acute lung injury (ALI), either via tracheotomy (INV) or non-invasively (NIV). There were a total of six conditions, applied in a non-randomized fashion: INV-RES1, INV-CO2, NIV-CO2, NIV-RES2, NIV-ALI, INV-ALI. For each condition, tNAVA was applied first (3 min), followed by 3 min of cNAVA. This comparison was repeated 3 times (repeated cross-over design). The NAVA level was always the same for both modes, but was newly titrated for each condition. PEEP was manually set to zero during tNAVA. During cNAVA, the assist during expiration was proportional to the EAdi. During all runs and conditions, ventilator-delivered pressure (Pvent), esophageal pressure (Pes), and diaphragm electrical activity (EAdi) were measured continuously. The tracings were analyzed breath-by-breath to obtain peak inspiratory and mean expiratory values.
For the same peak Pvent, the distribution of inspiratory and expiratory pressure differed between tNAVA and cNAVA. For each condition, the mean expiratory Pvent was always higher (for all conditions 4.0 ± 1.1 vs. 1.1 ± 0.5 cmH2O, P < 0.01) in cNAVA than in tNAVA. Relative to tNAVA, mean inspiratory EAdi was reduced on average (for all conditions) by 19 % (range 14 %–25 %), p < 0.05. Mean expiratory EAdi was also lower during cNAVA (during INV-RES1, INV-CO2, INV-ALI, NIV-CO2 and NIV-ALI respectively, P < 0.05). The inspiratory Pes was reduced during cNAVA all 6 conditions (p < 0.05). Unlike tNAVA, during cNAVA the expiratory pressure was comparable with that predicted mathematically (mean difference of 0.2 ± 0.8 cmH2O).
Continuous NAVA was able to apply neurally adjusted PEEP, which led to a reduction in inspiratory effort compared to triggered NAVA.
Most patients with sepsis and acute lung injury require mechanical ventilation to improve oxygenation and facilitate organ repair. Mast cells are important in response to infection and resolution of tissue injury. Since tryptase secreted from mast cells has been associated with tissue fibrosis, we hypothesized that tryptase would be involved in the early development of ventilator-induced pulmonary fibrosis in a clinically relevant model of sepsis-induced lung injury.
Prospective, randomized, controlled animal study using Sprague-Dawley rats. Sepsis was induced by cecal ligation and perforation. Animals were randomized to spontaneous breathing or two ventilatory strategies for 4 h: protective ventilation with tidal volume (VT) = 6 ml/kg plus 10 cmH2O positive end-expiratory pressure (PEEP) or injurious ventilation with VT = 20 ml/kg plus 2 cmH2O PEEP. Healthy, non-ventilated animals served as non-septic controls. We studied the following end points: histology, serum cytokine levels, hydroxyproline content, tryptase and proteinase-activated receptor-2 (PAR-2) protein level in lung homogenates, and tryptase and PAR-2 immunohistochemical localization in the lungs.
All septic animals developed acute lung injury. Animals ventilated with high VT had a significant increase of pulmonary fibrosis, hydroxyproline content, tryptase and PAR-2 protein levels compared to septic controls (P <0.0001). However, protective ventilation attenuated sepsis-induced lung injury and decreased lung tryptase and PAR-2 protein levels. Immunohistochemical staining confirmed the presence of tryptase and PAR-2 in the lungs.
Mechanical ventilation modified tryptase and PAR-2 in injured lungs. Increased levels of these proteins were associated with development of sepsis and ventilator-induced pulmonary fibrosis early in the course of sepsis-induced lung injury.
We previously showed in animals that the ratio of inspired tidal volume (Vtinsp) to inspiratory peak electrical activity of the diaphragm (EAdipk) can be used to quantify the respective patient and ventilator breath contributions (PVBCs) during neurally adjusted ventilatory assist (NAVA). The PVBC index has not been tested clinically.
We studied 12 intubated and mechanically ventilated patients with acute respiratory failure and measured EAdipk, airway (Paw) and inspiratory esophageal pressure (Pes) and Vtinsp. We applied 11 different NAVA levels, increasing them every 3 minutes in steps of 0.3 cm H2O/μV from 0 to 3.0 cmH2O/μV. At each NAVA level, one breath was non-assisted (NAVA level 0). PVBC indices were calculated by relating Vtinsp/EAdipk of the non-assisted breath to Vtinsp/EAdipk of the assisted breath(s) using one (N1PVBC) or the mean value of five preceding assisted breaths (X5PVBC). During assisted breaths, inspiratory changes in Pes (∆Pes) and transpulmonary (ΔPtp) pressures were used to calculate the relative contribution of patient to total inspiratory lung-distending pressures (ΔPes/ΔPtp). Matching of respiratory drive indices and squaring of the PVBC was evaluated for their effect on the correlation between PVBC and ΔPes/ΔPtp. Linear regression analysis and Bland-Altman analysis were applied to compare indices.
Using an average of five assisted breaths prior to the non-assisted breath and squaring the PVBC (X5PVBC2) improved determination coefficients (P <0.05), adjusted the regression slope and intercept between PVBC and ΔPes/ΔPtp toward identity (P <0.05) and reduced bias (P <0.05). Matching EAdipk between non-assisted and assisted breaths within the range of 0.77 to 1.30 improved the relationship between X5PVBC2 and ΔPes/ΔPtp (P <0.05) and abolished the need for EAdi normalization in the PVBC calculation (R2 = 0.96; bias = 0.16 ± 0.06; precision = 0.33 ± 0.08 (mean and 95% confidence interval)).
This clinical study confirms previous experimental results showing that the PVBC2 predicts the contribution of the inspiratory muscles versus that of the ventilator during NAVA, when differences in effort (EAdi) between non-assisted and assisted breaths are limited. PVBC could help to quantify and standardize the adjustment of the level of assist, and hence reduce the risks of excessive ventilatory assist in patients.
ClinicalTrials.gov NCT01663480. Registered 9 August 2012.
Alveolar epithelial type II (AEII) cells are a key structure and defender in the lung but also are the targets in many lung diseases, including acute respiratory distress syndrome, ventilator-induced lung injury, and pulmonary fibrosis. We sought to establish an optimized method for high yielding and long maintenance of characteristics of primary human AEII cells to facilitate the investigation of the mechanisms of lung diseases at the cellular and molecular levels. Adult human peripheral normal lung tissues of oncologic patients undergoing lung resection were collected. The AEII cells were isolated and identified by the expression of pro-surfactant protein (SP)C, epithelial sodium channel (αENaC) and cytokeratin (CK)-8, the lamellar bodies specific for AEII cells, and confirmed by the histology using electron microscopy. The phenotype of AEII cells was characterized by the expression of surfactant proteins (SP-A, SP-B, SP-C, SP-D), CK-8, KL-6, αENaC, and aquaporin (AQP)-3, which was maintained over 20 days. The biological activity of the primary human AEII cells producing SP-C, cytokines, and intercellular adhesion molecule-1 was vigorous in response to stimulation with tumor necrosis factor-α. We have modified previous methods and optimized a method for isolation of high purity and long maintenance of the human AEII cell phenotype in primary culture. This method provides an important tool for studies aiming at elucidating the molecular mechanisms of lung diseases exclusively in AEII cells.
Human lung; lamellar bodies; surfactant proteins
Acute respiratory failure is a dominant feature of critical illness. In this review, we discuss 17 studies published last year in Critical Care. The discussion focuses on articles on several topics: respiratory monitoring, acute respiratory distress syndrome, noninvasive ventilation, airway management, secretion management and weaning.
The mechanisms of lung repair and fibrosis in the acute respiratory distress syndrome (ARDS) are poorly known. Since the role of WNT/β-catenin signaling appears to be central to lung healing and fibrosis, we hypothesized that this pathway is activated very early in the lungs after sepsis.
We tested our hypothesis using a three-step experimental design: (1) in vitro lung cell injury model with human bronchial epithelial BEAS-2B and lung fibroblasts (MRC-5) cells exposed to endotoxin for 18 hours; (2) an animal model of sepsis-induced ARDS induced by cecal ligation and perforation, and (3) lung biopsies from patients who died within the first 24 hours of septic ARDS. We examined changes in protein levels of target genes involved in the Wnt pathway, including WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, matrix metalloproteinase-7 (MMP7), cyclin D1, and vascular endothelial growth factor (VEGF) by Western blotting and immunohistochemistry. Finally, we validated the main gene targets of this pathway in experimental animals and human lungs.
Protein levels of WNT5A, non-phospho (Ser33/37/Thr41) β-catenin, total β-catenin, MMP7, cyclin D1, and VEGF increased after endotoxin stimulation in BEAS-2B and MRC-5 cells. Lungs from septic animals and from septic humans demonstrated acute lung inflammation, collagen deposition, and marked increase of WNT5A and MMP7 protein levels.
Our findings suggest that the WNT/β-catenin signaling pathway is activated very early in sepsis-induced ARDS and could play an important role in lung repair and fibrosis. Modulation of this pathway might represent a potential target for treatment for septic and ARDS patients.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0568-z) contains supplementary material, which is available to authorized users.
This review documents important progress made in 2013 in the field of critical care respirology, in particular with regard to acute respiratory failure and acute respiratory distress syndrome. Twenty-five original articles published in the respirology and critical care sections of Critical Care are discussed in the following categories: pre-clinical studies, protective lung ventilation – how low can we go, non-invasive ventilation for respiratory failure, diagnosis and prognosis in acute respiratory distress syndrome and respiratory failure, and promising interventions for acute respiratory distress syndrome.
Acute respiratory distress syndrome (ARDS) is characterized by overwhelming inflammatory responses and lung remodeling. We hypothesized that leukocyte infiltration during the inflammatory response modulates epithelial remodeling through a mechanism of epithelial-mesenchymal transition (EMT).
Human lung epithelial cells were treated for 30 min with hydrochloric acid (HCl). Human monocytes were then cocultured with the epithelial cells for up to 48 h, in the presence or absence of blocking peptides against lymphocyte function-associated antigen-1 (LFA-1), or tyrphostin A9, a specific inhibitor for platelet-derived growth factor (PDGF) receptor tyrosine kinase.
Exposure of lung epithelial cells to HCl resulted in increased expression of intercellular adhesion molecule-1 (ICAM-1) and production of interleukin (IL)-8 at 24 h. The expression of the epithelial markers E-cadherin decreased while the mesenchymal markers vimentin and α-smooth muscle actin (α-SMA) increased at 24 h and remained high at 48 h. The addition of monocytes augmented the profiles of lower expression of epithelial markers and higher mesenchymal markers accompanied by increased collagen deposition. This EMT profile was associated with an enhanced production of IL-8 and PDGF. Treatment of the lung epithelial cells with the LAF-1 blocking peptides CD11a237–246 or/and CD18112–122 suppressed monocyte adhesion, production of IL-8, PDGF and hydroxyproline as well as EMT markers. Treatment with tyrphostin A9 prevented the EMT profile shift induced by HCl stimulation.
The interaction between epithelial cells and monocytes enhanced epithelial remodelling after initial injury through EMT signalling that is associated with the release of soluble mediators, including IL-8 and PDGF.
ARDS; PDGF; Chemokine; EMT
Circadian rhythms are intrinsic timekeeping mechanisms that allow for adaptation to cyclic environmental changes. Increasing evidence suggests that circadian rhythms may influence progression of a variety of diseases as well as effectiveness and toxicity of drugs commonly used in the intensive care unit. In this perspective, we provide a brief review of the molecular mechanisms of circadian rhythms and its relevance to critical care.
Data Sources, Study Selection, Data Extraction, and Data Synthesis
Articles related to circadian rhythms and organ systems in normal and disease conditions were searched through the PubMed library with the goal of providing a concise review.
Critically ill patients may be highly vulnerable to disruption of circadian rhythms as a result of the severity of their underlying diseases as well as the intensive care unit environment where noise and frequent therapeutic/diagnostic interventions take place. Further basic and clinical research addressing the importance of circadian rhythms in the context of critical care is warranted to develop a better understanding of the complex pathophysiology of critically ill patients as well as to identify novel therapeutic approaches for these patients.
PMID: 21926587 CAMSID: cams2913
clock gene; diurnal variation; inflammation
Mechanical ventilation is associated with overwhelming inflammatory responses that are associated with ventilator- induced lung injury (VILI) in patients with acute respiratory distress syndrome. The activation of adenosine A2A receptors has been reported to attenuate inflammatory cascades.
The administration of A2A receptors agonist ameliorates VILI.
Rats were subjected to hemorrhagic shock and resuscitation as a first hit to induce systemic inflammation. The animals randomly received the selective A2A receptor agonist CGS-21680 or a vehicle control in a blinded fashion at the onset of resuscitation phase. They were then randomized to receive mechanical ventilation as a second hit with a high tidal volume of 20 mL/kg and zero positive end-expiratory pressure, or a low tidal volume of 6 mL/kg with positive end-expiratory pressure of 5 cm H2O.
The administration of CGS-21680 attenuated lung injury as evidenced by a decrease in respiratory elastance, lung edema, lung injury scores, neutrophil recruitment in the lung, and production of inflammatory cytokines, compared with the vehicle treated animals.
The selective A2A receptor agonist may have a place as a novel therapeutic approach in reducing VILI.
PMID: 19487932 CAMSID: cams2915
acute respiratory distress syndrome; inflammation; neutrophils
Experimental work provides insight into potential lung protective strategies. The objective of this study was to evaluate markers of ventilator-induced lung injury after two different ventilation approaches: (1) a “conventional” lung-protective strategy (volume control (VC) with low tidal volume, positive end-expiratory pressure (PEEP) and paralysis), (2) a physiological approach with spontaneous breathing, permitting synchrony, variability and a liberated airway. For this, we used non-invasive Neurally Adjusted Ventilatory Assist (NIV-NAVA), with the hypothesis that liberation of upper airways and the ventilator’s integration with lung protective reflexes would be equally lung protective.
In this controlled and randomized in vivo laboratory study, 25 adult White New Zealand rabbits were studied, including five non-ventilated control animals. The twenty animals with aspiration-induced lung injury were randomized to ventilation with either VC (6 mL/kg, PEEP 5 cm H2O, and paralysis) or NIV-NAVA for six hours (PEEP = zero because of leaks). Markers of lung function, lung injury, vital signs and ventilator parameters were assessed.
At the end of six hours of ventilation (n = 20), there were no significant differences between VC and NIV-NAVA for vital signs, PaO2/FiO2 ratio, lung wet-to-dry ratio and broncho-alveolar Interleukin 8 (Il-8). Plasma IL-8 was higher in VC (P <0.05). Lung injury score was lower for NIV-NAVA (P = 0.03). Dynamic lung compliance recovered after six hours in NIV-NAVA but not in VC (P <0.05). During VC, peak pressures increased from 9.2 ± 2.4 cm H2O (hour 1) to 12.3 ± 12.3 cm H2O (hour 6) (P <0.05). During NIV-NAVA, the tracheal end-expiratory pressure was similar to the end-expiratory pressure during VC. Two animals regurgitated during NIV-NAVA, without clinical consequences, and survived the protocol.
In experimental acute lung injury, NIV-NAVA is as lung-protective as VC 6 ml/kg with PEEP.
Electronic supplementary material
The online version of this article (doi:10.1186/cc13706) contains supplementary material, which is available to authorized users.
Rationale: Patients who developed acute respiratory distress syndrome (ARDS) after infection with severe respiratory viruses (e.g., severe acute respiratory syndrome–coronavirus, H5N1 avian influenza virus), exhibited unusually high levels of CXCL10, which belongs to the non-ELR (glutamic-leucine-arginine) CXC chemokine superfamily. CXCL10 may not be a bystander to the severe virus infection but may directly contribute to the pathogenesis of neutrophil-mediated, excessive pulmonary inflammation.
Objectives: We investigated the contribution of CXCL10 and its receptor CXCR3 axis to the pathogenesis of ARDS with nonviral and viral origins.
Methods: We induced nonviral ARDS by acid aspiration and viral ARDS by intratracheal influenza virus infection in wild-type mice and mice deficient in CXCL10, CXCR3, IFNAR1 (IFN-α/β receptor 1), or TIR domain-containing adaptor inducing IFN-β (TRIF).
Measurements and Main Results: We found that the mice lacking CXCL10 or CXCR3 demonstrated improved severity and survival of nonviral and viral ARDS, whereas mice that lack IFNAR1 did not control the severity of ARDS in vivo. The increased levels of CXCL10 in lungs with ARDS originate to a large extent from infiltrated pulmonary neutrophils, which express a unique CXCR3 receptor via TRIF. CXCL10-CXCR3 acts in an autocrine fashion on the oxidative burst and chemotaxis in the inflamed neutrophils, leading to fulminant pulmonary inflammation.
Conclusions: CXCL10-CXCR3 signaling appears to be a critical factor for the exacerbation of the pathology of ARDS. Thus, the CXCL10-CXCR3 axis could represent a prime therapeutic target in the treatment of the acute phase of ARDS of nonviral and viral origins.
CXCL10; CXCR3; ARDS