Development Of ALI Research Articles

The role of FPR2-mediated ferroptosis in formyl peptide-induced acute lung injury against endothelial barrier damage and protective effect of the mitochondria-derived peptide MOTS-c

BackgroundAcute lung injury (ALI) has garnered significant attention in the field of respiratory and critical care due to its high mortality and morbidity, and limited treatment options. The role of the endothelial barrier in the development of ALI is crucial. Several bacterial pathogenic factors, including the bacteria-derived formyl peptide (fMLP), have been implicated in damaging the endothelial barrier and initiating ALI. However, the mechanism by which fMLP causes ALI remains unclear. In this study, we aim to explore the mechanisms of ALI caused by fMLP and evaluate the protective effects of MOTS-c, a mitochondrial-derived peptide. MethodsWe established a rat model of ALI and a human pulmonary microvascular endothelial cell (HPMVEC) model of ALI by treatment with fMLP. In vivo experiments involved lung histopathology assays, assessments of inflammatory and oxidative stress factors, and measurements of ferroptosis-related proteins and barrier proteins to evaluate the severity of fMLP-induced ALI and the type of tissue damage in rats. In vitro experiments included evaluations of fMLP-induced damage on HPMVEC using cell activity assays, assessments of inflammatory and oxidative stress factors, measurements of ferroptosis-related proteins, endothelial barrier function assays, and examination of the key role of FPR2 in fMLP-induced ALI. We also assessed the protective effect of MOTS-c and investigated its mechanism on the fMLP-induced ALI in vivo and in vitro. ResultsResults from both in vitro and in vivo experiments demonstrate that fMLP promotes the expression of inflammatory and oxidative stress factors, activates ferroptosis and disrupts the vascular endothelial barrier, ultimately contributing to the development and progression of ALI. Mechanistically, ferroptosis mediated by FPR2 plays a key role in fMLP-induced injury, and the Nrf2 and MAPK pathways are involved in this process. Knockdown of FPR2 and inhibition of ferroptosis can attenuate ALI induced by fMLP. Moreover, MOTS-c could protect the vascular endothelial barrier function by inhibiting ferroptosis and suppressing the expression of inflammatory and oxidative stress factors through Nrf2 and MAPK pathways, thereby alleviating fMLP-induced ALI. ConclusionOverall, fMLP disrupts the vascular endothelial barrier through FPR2-mediated ferroptosis, leading to the development and progression of ALI. MOTS-c demonstrates potential as a protective treatment against ALI by alleviating the damage induced by fMLP.

Endothelium-Derived Engineered Extracellular Vesicles Protect the Pulmonary Endothelial Barrier in Acute Lung Injury.

Acute lung injury (ALI) is a severe respiratory disease with a high mortality rate. The integrity of the pulmonary endothelial barrier influences the development and prognosis of ALI. Therefore, it has become an important target for ALI treatment. Extracellular vesicles (EVs) are promising nanotherapeutic agents against ALI. Herein, endothelium-derived engineered extracellular vesicles (eEVs) that deliver microRNA-125b-5p (miRNA-125b) to lung tissues exerting a protective effect on endothelial barrier integrity are reported. eEVs that are modified with lung microvascular endothelial cell-targeting peptides (LET) exhibit a prolonged retention time in lung tissues and targeted lung microvascular endothelial cells in vivo and in vitro. To improve the efficacy of the EVs, miRNA-125b is loaded into EVs. Finally, LET-EVs-miRNA-125b is constructed. The results show that compared to the EVs, miRNA-125b, and EVs-miRNA-125b, LET-EVs-miRNA-125b exhibit the most significant treatment efficacy in ALI. Moreover, LET-EVs-miRNA-125b is found to have an important protective effect on endothelial barrier integrity by inhibiting cell apoptosis, promoting angiogenesis, and protecting intercellular junctions. Sequencing analysis reveals that LET-EVs-miRNA-125b downregulates early growth response-1 (EGR1)levels, which may be a potential mechanism of action. Taken together, these findings suggest that LET-EVs-miRNA-125b can treat ALI by protecting the endothelial barrier integrity.

Ferroptosis-related signature and immune infiltration characterization in acute lung injury/acute respiratory distress syndrome

BackgroundAcute lung injury/acute respiratory distress syndrome (ALI/ARDS) is one of the most life-threatening diseases in the intensive care unit with high mortality and morbidity. Ferroptosis is a newly discovered immune related cell death that is associated with various lung diseases. However, the role of immune-mediated ferroptosis in ALI/ARDS has not been elucidated.MethodWe analyzed two Gene Expression Omnibus (GEO) datasets (GSE2411 and GSE109913) and extracted characteristic ferroptosis-related genes (FRGs) between the control and ALI groups through bioinformatic analysis. Then, we prospectively collected bronchoalveolar lavage fluid (BALF) from patients with ARDS and verified the expression of characteristic FRGs. Lastly, we constructed the ALI/ARDS model induced by LPS and isolated the primary neutrophils of mice. Erastin, an ferroptosis inducer, was used at the cellular level to verify the effect of neutrophils on ferroptosis in lung epithelium cells.ResultWe identified three characteristic FRGs, Cp, Slc39a14 and Slc7a11, by analyzing two gene expression profiling datasets. Immune infiltration analysis showed that the three characteristic genes were significantly positively correlated with the infiltration levels of neutrophils. We collected BALF from 59 ARDS patients to verify the expression of Cp, Slc7a11 and Slc39a14 in humans. The results showed that Cp was elevated in patients with severe ARDS (p = 0.019), Slc7a11 was significantly elevated in patients with moderate ARDS (p = 0.021) relative to patients with mild ARDS. The levels of neutrophils in the peripheral blood of ARDS patients were positively correlated with the expression levels of Slc7a11 (Pearson’s R2 = 0.086, p = 0.033). Three characteristic FRGs were significantly activated after the onset of ferroptosis (6 h) early in LPS induced ALI model, and that ferroptosis was alleviated after the organism compensated within 12 to 48 h. We extracted primary activated neutrophils from mice and co-cultured them with MLE-12 in transwell, Slc7a11, Cp and Slc39a14 in MLE-12 cells were significantly upregulated as the number of neutrophils increased. The results showed that neutrophil infiltration alleviated erastin-induced MDA accumulation, GSH depletion, and divalent iron accumulation, accompanied by upregulation of Slc7a11 and Gpx4, implying the existence of a compensatory effect of lipid oxidation in neutrophils after acute lung injury in the organism.ConclusionWe identified three immune-mediated ferroptosis genes, namely, Cp, Slc7a11 and Slc39a14, which possibly regulated by neutrophils during the development of ALI, and their pathways may be involved in anti-oxidative stress and anti-lipid metabolism. Thus, the present study contributes to the understanding of ALI/ARDS and provide novel targets for future immunotherapeutic.

GPR84 regulates pulmonary inflammation by modulating neutrophil functions

Acute lung injury (ALI) is an acute, progressive hypoxic respiratory failure that could develop into acute respiratory distress syndrome (ARDS) with very high mortality rate. ALI is believed to be caused by uncontrolled inflammation, and multiple types of immune cells, especially neutrophils, are critically involved in the development of ALI. The treatment for ALI/ARDS is very limited, a better understanding of the pathogenesis and new therapies are urgently needed. Here we discover that GPR84, a medium chain fatty acid receptor, plays critical roles in ALI development by regulating neutrophil functions. GPR84 is highly upregulated in the cells isolated from the bronchoalveolar lavage fluid of LPS-induced ALI mice. GPR84 deficiency or blockage significantly ameliorated ALI mice lung inflammation by reducing neutrophils infiltration and oxidative stress. Further studies reveal that activation of GPR84 strongly induced reactive oxygen species production from neutrophils by stimulating Lyn, AKT and ERK1/2 activation and the assembly of the NADPH oxidase. These results reveal an important role of GPR84 in neutrophil functions and lung inflammation and strongly suggest that GPR84 is a potential drug target for ALI.

FEATURES OF THE COURSE OF COVID-19 IN WOMEN WITH HYPERPROLACTINEMIA

The 2019 coronavirus pandemic is a major stressful event. In turn, stressful situations are triggers for the exacerbation of existing and activation of new diseases caused by a violation of the immune response in the human body and the development of inflammatory diseases. A stressful state causes the release of stress-mediated hormones, which in turn contributes to an increase in the level of PRL. Obviously, it is a closed circle. Therefore, the questions become relevant: 1. Can stress against the background of Covid-19 really cause an increase in the level of PRL? 2. Can Sovid-19 worsen the course of an already existing HP? Purpose: to conduct an analysis of available medical research on the peculiarities of the course of Covid-19 in women with HP, highlighting research on this topic in order to systematize new views on the diagnosis and treatment of Covid-19 against the background of already existing HP. Materials and methods. 10 articles from 2018 to 2022 with the keywords prolactin, hyperprolactinemia and Covid-19 were analyzed. Research results and their discussion. A review and analysis of a closed cohort study in which 30 men and 15 women participated and passed the Trier social stress test showed that PRL levels were significantly increased in response to a stressor [10], which could be the Covid-19 pandemic. In SARS-CoV-2, the defined receptor binding domain of the viral membrane protein uses angiotensin-converting enzyme 2 (ACE2) as a receptor for virus-host membrane fusion [2]. ACE2 regulates the activity of dopamine decarboxylase (DDC), which is responsible for the synthesis of dopamine and serotonin. Thus, SARS-CoV-2 disrupts the biosynthesis of dopamine, which leads to an increase in the level of PRL. With Covid-19, the expression of TLR4 and NF-κB is activated and increases the induction release of pro-inflammatory cytokines with the development of ALI, ARDS and cytokines with MOF. Conclusions Based on the studies described above, it can be concluded that Covid-19 inhibits the synthesis of dopamine and thus increases the level of prolactin. Also, prolactin can exhibit both
 immunostimulating and immunosuppressive, as well as pro-inflammatory and anti-inflammatory effects. Treatment with agonists of dopamine receptors can lead to deepening of depression in Covid-19. Treatment of hyperprolactinemia should be carried out with caution, because in critically ill patients who require personal support, the use of amine derivatives with DRA can cause additional vasospasm and, as a result, a rapid increase in blood pressure.

The role of ferroptosis in acute lung injury.

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is a common disease with high morbidity and mortality, and its pathogenesis is believed to be related to oxidative stress, apoptosis, inflammation, and hypoxia. Ferroptosis is a type of nonapoptotic cell death characterized by iron-dependent lipid peroxide accumulation and is involved in many cellular physiological processes. Recent studies have confirmed that ferroptosis may be involved in the development of ALI. This review summarizes the most recent discoveries on the role of ferroptosis in ALI to provide new strategies for its prevention and treatment.

PIM1 inhibition attenuated endotoxin-induced acute lung injury through modulating ELK3/ICAM1 axis on pulmonary microvascular endothelial cells.

The dysfunction of pulmonary microvascular endothelial cells (PMVECs) is one of the critical characteristics of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) induced by severe infection. PIM1 is a constitutively active serine/threonine kinase that is involved in multiple biological processes. However, the underlying correlation between PIM1 and PMVECs injury remains unclear. The main purpose of this study was to reveal roles of PIM1 and explore the potential mechanisms during the development of endotoxin-induced ALI induced by intraperitoneal LPS administration. PIM1 level in the lung tissues of endotoxin-induced ALI mice or plasma derived from cardiopulmonary bypass (CPB)-induced ALI patients were measured. The protective roles of PIM1 specific inhibitor SMI-4a on endotoxin-induced lung injuries were evaluated through histological, permeability, neutrophil infiltration and survival assessment. The relationship between PIM1 and ELK3/ICAM-1 axis was validated in vivo and vitro. The correlation between plasma PIM1 and indicative vascular endothelium injury biomarkers (PaO2/FiO2 ratio, Ang-II, E-selectin and PAI-1) levels derived from CPB-induced ALI patient were analyzed. PIM1 expression in the lung tissues was increased in the mice of endotoxin-induced ALI. The PIM1 specific inhibitor SMI-4a administration relieved the severity of endotoxin-induced ALI. More importantly, PIM1 modulates ICAM1 expression through regulating transcription factor ELK3 expression in vitro. Eventually, plasma PIM1 level was positively correlated with Ang-II and PAI-1 levels but negatively correlated with SpO2/FiO2 ratio among CPB induced ALI patients. Our results indicated that PIM1 inhibition carried a protective role against endotoxin-induced ALI by modulating the ELK3/ICAM1 axis on PMVECs. PIM1 may be a potential therapeutic target for endotoxin-induced ALI.

Inhibition of myeloid differentiation factor 2 by baicalein protects against acute lung injury

BackgroundALI/ARDS is characterized by severe hypoxemic respiratory failure attributed to inflammatory tissue injury. There are no treatment modalities able to prevent/reverse the dire pathological sequelae in these patients. Evidence links the inflammatory lung injury to uncontrolled activation of the immune signaling complex, TLR4-MD2 (Toll-like receptor-myeloid differentiation factor 2). Baicalein, a natural flavonoid, is reported to have robust anti-inflammatory properties, but its inhibition mechanism remains unclear. Hypothesis/PurposeThis study investigated the protective mechanisms of baicalein on ALI/ARDS. MethodsWe used two experimental mouse models of LPS-induced ALI, pulmonary infection model (intratracheal LPS), and systemic infection model (intravenous LPS). Blood, BALF, lung and liver tissues were analyzed using routine methods. In vitro studies using peritoneal mouse macrophages or recombinant proteins were designed to elucidate inhibition mechanisms of baicalein. ResultsOur critical new findings revealed that Baicalein was an MD2 inhibitor, directly bound to MD2, effectively suppressing TLR4-MD2 activation and the subsequent MAPK and NF-κB signaling. The inhibited MD2 prevented development of inflammatory tissue injury and improved survival. The importance of MD2 in the inflammatory injury in ALI was corroborated by data obtained from MD2−/− mice, which did not develop the characteristic LPS-induced lung tissue damage. Thus, the findings indicated that MD2 was critical for development of ALI, functioning as an early upstream signal driving the progression of inflammatory injury. ConclusionBaicalein, as a direct and selective MD2 inhibitor, inhibited the early upstream TLR4-MD2 signaling and is a promising therapeutic agent for the treatment of ALI/ARDS.

TLR4-Upregulated IL-1β and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism.

Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary infection. Alveolar macrophages (AM) are at the center of the pathogenesis of the development of ALI. Interleukin-1β (IL-1β) is one of the key pro-inflammatory mediators, and its maturation is tightly controlled by the formation and activation of the inflammasome. The biological effects of IL-1β are mediated through IL-1 receptor (IL-1R). In this study, we investigated the influence of LPS-induced IL-1β release and IL-1RI upregulation on the development of lung inflammation. We demonstrated that in AM, LPS-TLR4 signaling not only activates Nlrp3 inflammasome activation and subsequent release of IL-1β, but also up-regulates IL-1RI expression on AM surface through MyD88 and NF-κB dependent signaling. The upregulated IL-1RI, therefore, sensitizes AM to IL-1β and results in pyroptosome formation, which in turn leads to AM pyroptosis, a type of caspase-1-dependent inflammatory cell death. We further showed that AM pyroptosis exaggerates lung inflammation. The present study demonstrates a novel mechanism underlying LPS-induced innate immunity; that is, a secondary upregulation of IL-1β-IL-1RI signaling is responsible for AM pyroptosis and augmented lung injury in response to LPS.

Activation of AMPK attenuates LPS-induced acute lung injury by upregulation of PGC1α and SOD1.

Evidence suggests that an imbalance between oxidation and antioxidation is involved in the pathogenesis of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). Activation of AMP-activated protein kinase (AMPK) has been shown to inhibit the occurrence of ALI/ARDS. However, it is unknown whether activation of AMPK benefits ALI/ARDS by restoration of the oxidant and antioxidant balance, and which mechanisms are responsible for this process. The present study aimed to address these issues. Lipopolysaccharide (LPS) induced pronounced pathological changes of ALI in mice; these were accompanied by elevated production of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) compared with control mice. Prior treatment of mice with the AMPK agonist metformin significantly suppressed the LPS-induced development of ALI, reduced the elevation of MDA and increased the activity of SOD. Further analysis indicated that activation of AMPK also stimulated the protein expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and superoxide dismutase 1 (SOD1). This study suggests that activation of AMPK by metformin inhibits oxidative stress by upregulation of PGC1α and SOD1, thereby suppressing the development of ALI/ARDS, and has potential value in the clinical treatment of such conditions.

Activation of PPARγ attenuates LPS-induced acute lung injury by inhibition of HMGB1-RAGE levels

HMGB1-RAGE signaling pathway is involved in the development of ALI/ARDS. At the same time, activation of PPARγ has been shown to inhibit the occurrence of ALI/ARDS. However, it is unknown whether activation of PPARγ benefits ALI/ARDS by regulation of HMGB1-RAGE signaling. This study aims to address these issues. We found in this study that LPS induced dramatic pathological changes of ALI in mice; these were accompanied with elevated expression of HMGB1 and RAGE. Prior treatment of mice with PPARγ agonist rosiglitazone significantly suppressed LPS-induced ALI and reversed the elevation of HMGB1 and RAGE; these were accompanied with the induction of HO-1. The presence of selective HO-1 inhibitor Znpp abolished the protective effects of rosiglitazone on LPS-induced ALI. This study suggests that activation of PPARγ inhibits the development of LPS-induced ALI by negative modulation of HMGB1-RAGE pathway, and has a potential value in the clinical treatment of such conditions.

S39 Human mesenchymal stem cells modulate alveolar macrophage polarisationIn vivoandin vitro

Rationale ALI is characterised by dysregulated and excessive pulmonary inflammation. Macrophages are key cellular mediators of the lung innate immune response. It is recognised that macrophages can be polarised towards an M1 (implicated in driving inflammation and the development of ALI) or an M2 (responsible for the resolution of inflammation) phenotype. We have previously reported that bone marrow-derived mesenchymal stem cell (MSC) treatment is protective in several models of ALI. To effectively translate MSCs into clinical practice, a better understanding of the mechanisms mediating their effect is needed. The current studies were undertaken to test if human MSCs have a role in polarising alveolar macrophages towards an M2 phenotype In vivo and in vitro . Methods In vivo studies were preformed using a mouse model of E.coli pneumonia. C57BL/6 mice were administered 10 6 CFU of E. coli intratracheally (IT), treatment with MSC was given IT 4 h later. BAL cytokine levels were measured by ELISA. For in vitro studies MSC and AM were co-cultured without cell contact, using a Transwell system. Expression of cell surfaceCD206 (mannose receptor, widely accepted to be a marker for M2 activation) and phagocytic activity were assessed by Flow Cytometry both In vivo and in vitro . Results In the In vivo model of E.coli pneumonia, hMSC treatment demonstrated reduction in the severity of lung injury, improved bacterial clearance and reduced TNF-α levels in the BAL 24 h after infection, compare to PBS-treated animals. hMSC administration was associated with significant up-regulation of CD206 on AM ( Figure 1 ). In addition, in vitro co-culture with hMSC markedly decreased LPS-induced TNF-α secretion by mouse AM, significantly up-regulated their expression of CD206 and enhanced their phagocytic activity towards bacteria. Interestingly, co-culture with MSC was associated with marked up-regulation of AM expression of CD11b and CD11c, both of which (among other functions) mediate bacterial phagocytosis. Conclusions Bone marrow-derived hMSCs have the capacity to change the phenotype and functional properties of alveolar macrophages. hMSCs drive the polarisation of AMs towards a less inflammatory state but at the same time have the unique capacity to increase the capacity of AMs to phagocytose bacteria. Supported by NHLBI HL51854 (MAM)

P148 Aspirin therapy is associated with reduced mortality in patients with acute lung injury

IntroductionPlatelet activation has a role in the pathogenesis of ALI. Observational data suggests aspirin treatment may prevent the development of ALI in critically ill patients. However, it is unknown if...

Hydrogen sulfide donor regulates alveolar epithelial cell apoptosis in rats with acute lung injury

Background Acute lung injury (ALI) is a common syndrome associated with high morbidity and mortality in emergency medicine. Cell apoptosis plays a key role in the pathogenesis of ALI. Hydrogen sulfide (H2S) plays a protective role during acute lung injury. We designed this study to examine the role of H2S in the lung alveolar epithelial cell apoptosis in rats with ALI. Methods Sixty-nine male Sprague Dawley rats were used. ALI was induced by intra-tail vein injection of oleic acid (OA). NaHS solution was injected intraperitonally 30 minutes before OA injection as the NaHS pretreatment group. Single sodium hydrosulfide pretreatment group and control group were designed. Index of quantitative assessment (IQA), wet/dry weight (W/D) ratio and the percentage of polymorphonuclear leukocyte (PMN) cells in the bronchoalveolar lavage fluid (BALF) were determined. H2S level in lung tissue was measured by a sensitive sulphur electrode. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining and Fas protein was measured by immunohistochemical staining. Results The level of endogenous H2S in lung tissue decreased with the development of ALI induced by OA injection. Apoptosis and Fas protein in alveolar epithelial cells increased in the ALI of rats but NaHS lessened apoptosis and Fas protein expression in alveolar epithelial cells of rats with ALI. Conclusion Endogenous H2S protects rats from oleic acid-induced ALI, probably by inhibiting cell apoptosis.

Pretreatment with anti-flagellin serum delays acute lung injury in rats with sepsis

This study examined the reduction of sepsis-induced ALI by inhibition of flagellin-stimulated TLR5 signaling. Rats were randomly divided into three groups: one group served as the sham-operated group (control group), and the other two groups received the induction of sepsis (sepsis and treatment groups). The treatment group was injected with anti-flagellin serum before induction of sepsis. At 2, 4, 6, 12, 24, and 48 h following induction of sepsis (six time-point subgroups, n = 10 per subgroup), arterial PaO(2), wet/dry (W/D) lung weight ratios, levels of serum and BALF flagellin and TNF-α, pulmonary pathological alterations, and TLR5 mRNA expression in the lungs were examined. Compared to sham-operated rats, septic rats had: increased levels of serum and BALF flagellin at 6, 12, 24, and 48 h; reduced arterial PaO(2); elevated W/D lung weight ratio; increased serum and BALF TNF-α levels; and up-regulated TLR5 mRNA expression at 12, 24, and 48 h (P < 0.01). Pretreatment with anti-flagellin serum, however, significantly inhibited sepsis-associated declines in arterial PaO(2), increased W/D lung weight ratios, elevated serum and BALF TNF-α levels, and up-regulated TLR5 mRNA expression at 24 and 48 h (P < 0.01). Neutralizing the actions of circulating flagellin with anti-flagellin serum delayed the development of ALI in rats with sepsis.

Adiponectin Attenuates Lipopolysaccharide-Induced Acute Lung Injury through Suppression of Endothelial Cell Activation

Adiponectin (APN) is an adipose tissue-derived factor with anti-inflammatory and vascular protective properties whose levels paradoxically decrease with increasing body fat. In this study, APN's role in the early development of ALI to LPS was investigated. Intratracheal LPS elicited an exaggerated systemic inflammatory response in APN-deficient (APN(-/-)) mice compared with wild-type (wt) littermates. Increased lung injury and inflammation were observed in APN(-/-) mice as early as 4 h after delivery of LPS. Targeted gene expression profiling performed on immune and endothelial cells isolated from lung digests 4 h after LPS administration showed increased proinflammatory gene expression (e.g., IL-6) only in endothelial cells of APN(-/-) mice when compared with wt mice. Direct effects on lung endothelium were demonstrated by APN's ability to inhibit LPS-induced IL-6 production in primary human endothelial cells in culture. Furthermore, T-cadherin-deficient mice that have significantly reduced lung airspace APN but high serum APN levels had pulmonary inflammatory responses after intratracheal LPS that were similar to those of wt mice. These findings indicate the importance of serum APN in modulating LPS-induced ALI and suggest that conditions leading to hypoadiponectinemia (e.g., obesity) predispose to development of ALI through exaggerated inflammatory response in pulmonary vascular endothelium.

Effect of valproic acid on acute lung injury in a rodent model of intestinal ischemia reperfusion

ObjectivesAcute lung injury (ALI) can develop during the course of many clinical conditions, and is associated with significant morbidity and mortality. Valproic acid (VPA), a well-known anti-epileptic drug, has been shown to have anti-oxidant and anti-inflammatory effects in various ischemia/reperfusion (I/R) models. The purpose of this study was to investigate whether VPA could affect survival and development of ALI in a rat model of intestinal I/R. MethodsTwo experiments were performed. Experiment I: Male Sprague-Dawley rats (250–300g) were subjected to intestinal ischemia (1h) and reperfusion (3h). They were randomized into 2 groups (n=7 per group) 30min after ischemia: Vehicle (Veh) and VPA (300mg/kg, IV). Primary end-point for this study was survival over 4h from the start of ischemia. Experiment II: The histological and biochemical effects of VPA treatment on lungs were examined 3h (1h ischemia+2h reperfusion) after intestinal I/R injury (Veh vs. VPA, n=9 per group). An objective histological score was used to grade the degree of ALI. Enzyme linked immunosorbent assay (ELISA) was performed to measure serum levels of interleukins (IL-6 and 10), and lung tissue of cytokine-induced neutrophil chemoattractant (CINC) and myeloperoxidase (MPO). In addition, the activity of 8-isoprostane was analyzed for pulmonary oxidative damage. ResultsIn Experiment I, 4-h survival rate was significantly higher in VPA treated animals compared to Veh animals (71.4% vs. 14.3%, p=0.006). In Experiment II, ALI was apparent in all of the Veh group animals. Treatment with VPA prevented the development of ALI, with a reduction in the histological score (3.4±0.3 vs. 5.3±0.6, p=0.025). Moreover, compared to the Veh control group the animals from the VPA group displayed decreased serum levels of IL-6 (952±213pg/ml vs. 7709±1990pg/ml, p=0.011), and lung tissue concentrations of CINC (1188±28pg/ml vs. 1298±27pg/ml, p<0.05), MPO activity (368±23ng/ml vs. 490±29ng/ml, p<0.05) and 8-isoprostane levels (1495±221pg/ml vs. 2191±177pg/ml, p<0.05). ConclusionVPA treatment improves survival and attenuates ALI in a rat model of intestinal I/R injury, at least in part, through its anti-oxidant and anti-inflammatory effects.

Association of the 1580 (C/T) Polymorphism in the Surfactant Protein B Gene with the Severity of Respiratory Failure after Allogeneic Transplantation.

Respiratory failure is a serious early complication confounding the clinical effect of allogeneic stem cell transplantation and early detection may be crucial for efficient treatment. We introduced a system of intensive oxigenation monitoring in patients transplanted in our center between November 2001 and December 2003. All allogeneic transplanted patients were followed by a twice daily measurement of oxi-index (paO2/FiO2) during the transplantation period (untill day + 25). Patients that fulfilled criteria of acute lung injury (oxi-index <300) were treated by O2 application vs. non-invasive ventilation (NIV). Failure to increase oxi-index above the threshold of 300 led to referral of the patient to ICU were intensified NIV was applied and/or mechanical ventilation (MV) was initiated based on a defined scoring system. 165 patients were followed for the development of ALI. 48 (29.1%) developed oxiindices <300 (ALI). Development of ALI predicted for a significantly higher rate of ICU admissions (37.5% vs. 6.8% in non-ALI patients; p<0.001) and MV (20.8 % vs. 1.7 in non-ALI patients; p<0.001). ALI was most commonly diagnosed during the engraftment period but was at diagnosis not associated with other criteria like respiration rate, CRP and tachycardia. Since members of the pulmonary innate immune system may be associated with the development of ALI and ARDS we screened the 165 patients for the presence of alternative alleles in the Surfactant Protein B (SP-B) gene. A polymorphism at position +1580 (T/C variation) of SP-B has been previously found to be associated with the development of ARDS. Polymorphism of SP-B were not associated with the development of ALI and did not predict for the need of intensified ICU treatment. However, the rate of MV varied considerably. Nine patients with the T/T genotype (9 out of 42, 21.4%) required intubation and mechanical ventilation whereas none of the patients with C/C had to receive MV (0 out of 30; p=0.01).The data indicate that measurement of the oxiindex is an early sensitive parameter of respiratory failure in allogeneic transplantation and that severity of respiratory damage may be predicted by the T allele at the SP-B +1580 site

Elevated plasma levels of soluble TNF receptors are associated with morbidity and mortality in patients with acute lung injury

Ventilator-induced lung injury (VILI) is an inflammatory process that can be attenuated by lung protective ventilation strategies. Our objectives to further investigate the pathogenesis of ALI and VILI and the mechanism of lung protection in these syndromes were: 1) to determine if plasma measurements of soluble TNF receptor I (sTNFRI) and II (sTNFRII) would predict the development of ALI and mortality in a small single center trial; 2) to test the predictive value of these markers and of TNF-alpha in a larger, broader group of patients with ALI; 3) to test the hypothesis that low tidal volume ventilation (LTVV) would be associated with a decrease in plasma levels of TNF-alpha, sTNFRI, and sTNFRII. In the single center study, sTNFRI and II levels were higher in patients at risk for and with ALI, but they did not predict the development of the syndrome. In the multicenter trial sTNFRI and II were strongly associated with mortality (OR 5.76/1 log10 increment in receptor level; 95% CI 2.63-12.6 and OR 2.58; 95% CI 1.05-6.31, respectively) and morbidity measured as fewer nonpulmonary organ failure-free and ventilator-free days. The LTVV strategy was associated with an attenuation of plasma sTNFRI levels. In vitro, stimulated A549 cells release sTNFRI but not sTNRFII. In conclusion, plasma levels of sTNFRI and II can serve as biomarkers for morbidity and mortality in patients with ALI. Furthermore, LTVV is associated with a specific decrease in sTNFRI levels. This suggests that one beneficial effect of LTVV may be to attenuate alveolar epithelial injury.

MEDIATORS AND MECHANISMS OF ACUTE LUNG INJURY

Since last reviewed in this forum, there have been remarkable advances in our understanding of the acute inflammatory process and how it contributes to the development of ALI. As stated in the beginning of this article, it is not possible to even begin to review all the specific advances that have been made. Instead, the author has focused on concepts that have emerged and improved our ability to study the pathogenesis of ARDS. These include the recognition that patients at risk for and with ARDS represent a heterogeneous population, that mediators or markers of inflammation cannot be considered in isolation, that a balance between proinflammatory mediators and inflammatory modulators may be important, and that there are several genetic factors that could contribute to the susceptibility for the development of ARDS. Hopefully these concepts can be expanded and clarified so that the next review of this topic can report on successful therapeutic interventions for the prevention and the treatment of ARDS.