Acute Respiratory Distress Syndrome/acute Lung Injury Research Articles

The link between neutrophils, neutrophil extracellular traps, and NLRP3 inflammasomes: The dual effect of CD177 and its therapeutic potential in acute respiratory distress syndrome/acute lung injury.

Neutrophils are important inflammatory effector cells that protect against foreign invasion but also cause self-harm. Numerous neutrophils infiltrate the lungs in acute respiratory distress syndrome/acute lung injury (ARDS/ALI) patients. However, the exact impact of neutrophil infiltration on ARDS's onset and progression remains unclear. To investigate this, we analyzed two ARDS-related datasets from the Gene Expression Omnibus public database and discovered an association between CD177, a neutrophil-specific surface protein, and ARDS progression. We used quantitative flow cytometry to assess CD177+ neutrophils in the peripheral blood of clinical ARDS patients versus healthy controls, finding a significant increase in CD177+ neutrophils percentage among total neutrophils in ARDS patients. This finding was further confirmed in ALI mouse models. Subsequent animal experiments showed that anti-CD177 effectively reduces pulmonary edema, neutrophil infiltration, and inflammatory cytokine release, along with a decrease in reactive oxygen species (ROS) and myeloperoxidase (MPO) levels. We also established an in vitro co-culture system to mimic neutrophil and lung epithelial cell interactions. In the anti-CD177 group, we observed decreased expression of NLRP3, caspase 1, PAD4, MPO, and ROS, along with a reduction in certain inflammatory cytokines. These results indicate a crucial role for the CD177 gene in ARDS's development and progression. Inhibiting CD177 may help mitigate excessive activation of NLRP3 inflammasomes, ROS, and neutrophil extracellular traps (NETs), thus alleviating ARDS.

PLD2 deletion alleviates disruption of tight junctions in sepsis-induced ALI by regulating PA/STAT3 phosphorylation pathway.

Increased inflammatory exudation caused by endothelium and endothelial junction damage is a typical pathological feature of acute respiratory distress syndrome/acute lung injury (ARDS/ALI). Previous studies have shown that phospholipase D2 (PLD2) can increase the inflammatory response and has a close relationship with the severity of sepsis-induced ALI and the mortality of sepsis, but its mechanism is unknown. This study explored the effect and mechanism of PLD2 deletion on the structure and function of endothelial tight junction (TJ) in lipopolysaccharide (LPS)-induced ALI. We used C57BL/6 mice (wild-type and PLD2 knockout (PLD2-/-)) and human umbilical vein endothelial cell (HUVEC) models of sepsis-ALI. The pathological changes were evaluated by hematoxylin-eosin staining. Pulmonary vascular permeability was detected using wet-dry ratio, fluorescein isothiocyanate (FITC)-dextran, FITC-albumin, and immunoglobulin M concentration of bronchoalveolar lavage fluid. FITC-dextran and trans-endothelial electrical resistance assay were used to evaluate endothelial permeability on LPS-stimulated HUVECs. The mRNA expressions of TJ proteins were detected by real-time quantitative polymerase chain reaction. Then, protein levels were detected through Western blot analysis and immunofluorescence. The content of phosphatidic acid (PA), a downstream product of PLD2, was detected using an enzyme-linked immunosorbent assay kit. PLD2 deficiency not only alleviated lung histopathological changes and improved pulmonary vascular permeability but also increased the survival rate of ALI mice. Knockout of PLD2 or treatment with the PLD2 inhibitor can reduce the damage of endothelial TJ proteins, namely, claudin5, occludin and zonula occludens protein-1, in sepsis-ALI mice and LPS-stimulated HUVECs. The level of the PLD2 catalytic product PA increased in LPS-stimulated HUVECs, and exogenous PA can reduce the TJ protein expression and increase signal transducer and activator of transcription 3 (STAT3) phosphorylation in vitro. Inhibition of STAT3 phosphorylation attenuated PA-induced degradation of endothelial TJs. PLD2 knockout or inhibition may protect against LPS-induced lung injury by regulating the PA/STAT3 phosphorylation/endothelial TJ axis.

Lpar1-mediated Effects in Endothelial Progenitor Cells Are Crucial for Lung Repair in Acute Respiratory Distress Syndrome/Acute Lung Injury.

Acute respiratory distress syndrome/acute lung injury (ARDS/ALI) involves acute respiratory failure characterized by vascular endothelial and lung alveolar epithelial injury. Endothelial progenitor cells (EPCs) can mediate vasculogenesis. However, the limitations of EPCs, such as low survival and differentiation, are believed to inhibit the effectiveness of autologous cell therapies. This study demonstrated that lysophosphatidic acid (LPA), a bioactive small molecule without immunogenicity, is involved in the survival and antiapoptotic effects in human umbilical cord mesenchymal stem cells. This study aimed to explore whether LPA improves the survival of EPCs, enhancing the cellular therapeutic efficacy in ARDS, and these results will expand the application of LPA in stem cells and regenerative medicine. LPA promoted the colony formation, proliferation, and migration of EPCs and upregulated the expression of vascular endothelial-derived growth factor (VEGF) in EPCs. LPA pretreatment of transplanted EPCs improved the therapeutic effect by increasing EPC numbers in the rat lungs. LPA enhanced EPC proliferation and migration through Lpar1 coupled to Gi/o and Gq/11, respectively. Activation of extracellular signal-related kinase 1/2, or ERK1/2, was related to LPA-induced EPC proliferation but not migration. LPA/Lpar1-mediated Gi/o protein was also shown to be involved in promoting VEGF expression and inhibiting IL-1α expression in EPCs. Low LPA concentrations are present after lung injury; thus, the restoration of LPA may promote endothelial cell homeostasis and lung repair in ARDS. Inhalation of LPA significantly promoted the homing of endogenous EPCs to the lung and reduced lung injury in both rats with LPS-induced ALI and Streptococcus pneumoniae-infected mice. Taken together, these data indicated that LPA/Lpar1-mediated effects in EPCs are involved in maintaining endothelial cell homeostasis and lung tissue repair under physiological conditions.

Ursolic acid and SARS-CoV-2 infection: a new horizon and perspective.

SARS-CoV-2 (severe acute respiratory syndrome coronavirus type 2) has been identified as the source of a world coronavirus pandemic in 2019. Covid-19 is considered a main respiratory disease-causing viral pneumonia and, in severe cases, leads to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Although, extrapulmonary manifestations of Covid-19 like neurological, cardiovascular, and gastrointestinal have been confirmed. Exaggerated immune response and release of a high amount of pro-inflammatory cytokines may progress, causing a cytokine storm. Consequently, direct and indirect effects of SARS-CoV-2 infection can evolve into systemic complications due to the progression of hyper inflammation, oxidative stress and dysregulation of the renin-angiotensin system (RAS). Therefore, anti-inflammatory and antioxidant agents could be efficient in alleviating these disorders. Ursolic acid has anti-inflammatory, antioxidant, and antiviral effects; it reduces the release of pro-inflammatory cytokines, improves anti-inflammatory cytokines, and inhibits the production of reactive oxygen species (ROS). In virtue of its anti-inflammatory and antioxidant effects, ursolic acid may minimize SARS-CoV-2 infection-induced complications. Also, by regulating RAS and inflammatory signaling pathways, ursolic acid might effectively reduce the development of ALI in ARDS in Covid-19. In this state, this perspective discusses how ursolic acid can mitigate hyper inflammation and oxidative stress in Covid-19.

The Effect of Chronic and Inhospital Exposure to Renin-Angiotensin System Inhibitors on the Outcome and Inflammatory State of Coronavirus Disease 2019 Adult Inpatients.

Background Controversies exist about the effect of renin-angiotensin system inhibitors (RASi) on coronavirus disease 2019 (COVID-19) outcome. The inhospital use of RASi and its effect on inflammatory sate are still poorly studied during the COVID-19 pandemic. Objectives We aimed to compare the impact of previous and inhospital RASi exposure on the outcome and inflammatory response of COVID-19 patients. Methods Single-centre, ambispective analysis of hospitalized adult COVID-19 patients at Hospital de Santa Maria, Lisbon, between March and August 2020 was performed. We excluded asymptomatic patients and those admitted due to another disease. The primary outcome was inhospital all-cause mortality. Illness severity was assessed based on the development of acute respiratory distress syndrome/acute lung injury (ARDS/ALI), intensive care unit (ICU) admission, and need for invasive mechanical ventilation (IMV). We used C-reactive protein (CRP), ferritin, and interleukin 6 (IL-6) as surrogate markers of the inflammatory response. Results From a total of 432 patients, 279 were selected, among whom 133 (47.7%) were receiving a RASi. Chronic treatment with RASi was not associated with the risk of death (OR 1.24, 95% CI 0.66–2.31, p=0.500), ARDS/ALI development (OR 1.12, 95% CI 0.67–1.86, p=0.676), ICU admission (OR 1.11, 95% CI 0.67–1.84, p = 0.686), and IMV need (OR 1.03, 95% CI 0.58–1.84, p=0.917) in a univariable and multivariable analysis. Inhospital RASi withdrawing was associated with the risk of death (OR 4.38, 95% CI 1.11–17.21, p=0.035) and ARDS/ALI development (OR 4.33, 95% CI 1.49–12.6, p=0.007), the latter remaining significant after adjustment. Previous exposure to RASi was associated with lower CRP levels at admission (p=0.018). IL-6 levels were significantly higher in those patients whose RASi were stopped (p=0.024). Conclusion Previous and inhospital exposure to RASi was not associated with mortality nor severity of COVID-19. This study supports current guidance on RASi management during the COVID-19 pandemic.

Protectin DX promotes epithelial injury repair and inhibits fibroproliferation partly via ALX/PI3K signalling pathway

Acute respiratory distress syndrome/acute lung injury (ARDS/ALI) is histologically characterized by extensive alveolar barrier disruption and excessive fibroproliferation responses. Protectin DX (PDX) displays anti‐inflammatory and potent inflammation pro‐resolving actions. We sought to investigate whether PDX attenuates LPS (lipopolysaccharide)‐induced lung injury via modulating epithelial cell injury repair, apoptosis and fibroblasts activation. In vivo, PDX was administered intraperitoneally (IP) with 200 ng/per mouse after intratracheal injection of LPS, which remarkedly stimulated proliferation of type II alveolar epithelial cells (AT II cells), reduced the apoptosis of AT II cells, which attenuated lung injury induced by LPS. Moreover, primary type II alveolar cells were isolated and cultured to assess the effects of PDX on wound repair, apoptosis, proliferation and transdifferentiation in vitro. We also investigated the effects of PDX on primary rat lung fibroblast proliferation and myofibroblast differentiation. Our result suggests PDX promotes primary AT II cells wound closure by inducing the proliferation of AT II cells and reducing the apoptosis of AT II cells induced by LPS, and promotes AT II cells transdifferentiation. Furthermore, PDX inhibits transforming growth factor‐β1 (TGF‐β1) induced fibroproliferation, fibroblast collagen production and myofibroblast transformation. Furthermore, the effects of PDX on epithelial wound healing and proliferation, fibroblast proliferation and activation partly via the ALX/ PI3K signalling pathway. These data present identify a new mechanism of PDX which targets the airway epithelial cell and fibroproliferation are potential for treatment of ARDS/ALI.

Targeting NOX4 alleviates sepsis-induced acute lung injury via attenuation of redox-sensitive activation of CaMKII/ERK1/2/MLCK and endothelial cell barrier dysfunction

Increased pulmonary vascular permeability due to endothelial cell (EC) barrier dysfunction is a major pathological feature of acute respiratory distress syndrome/acute lung injury (ARDS/ALI), which is a devastating critical illness with high incidence and excessive mortality. Activation of NADPH oxidase (NOX) induces EC dysfunction via production of reactive oxygen species (ROS). However, the role(s) of NOX isoform(s), and their downstream signaling events, in the development of ARDS/ALI have remained unclear. Cecal Ligation Puncture (CLP) was used to induce preclinical septic ALI in wild-type mice and mice deficient in NOX2 or p47phox, or mice transfected of control siRNA, NOX1 or NOX4 siRNA in vivo. The survival rate of the CLP group at 24 h (26.6%, control siRNA treated) was substantially improved by NOX4 knockdown (52.9%). Mice lacking NOX2 or p47phox, however, had worse outcomes after CLP (survival rates at 0% and 8.3% respectively), whereas NOX1-silenced mice had similar survival rate (30%). NOX4 knockdown attenuated lung ROS production in septic mice, whereas NOX1 knockdown, NOX2 knockout, or p47phox knockout in mice had no effects. In addition, NOX4 knockdown attenuated redox-sensitive activation of the CaMKII/ERK1/2/MLCK pathway, and restored expression of EC tight junction proteins ZO-1 and Occludin to maintain EC barrier integrity. Correspondingly, NOX4 knockdown in cultured human lung microvascular ECs also reduced LPS-induced ROS production, CaMKII/ERK1/2/MLCK activation and EC barrier dysfunction. Scavenging superoxide in vitro and in vivo with TEMPO, or inhibiting CaMKII activation with KN93, had similar effects as NOX4 knockdown in preserving EC barrier dysfunction. In summary, we have identified a novel, selective and causal role of NOX4 (versus other NOX isoforms) in inducing lung EC barrier dysfunction and injury/mortality in a preclinical CLP-induced septic model, which involves redox-sensitive activation of CaMKII/ERK1/2/MLCK pathway. Targeting NOX4 may therefore prove to an innovative therapeutic option that is markedly effective in treating ALI/ARDS.

Calreticulin Blockade Attenuates Murine Acute Lung Injury by Inducing Polarization of M2 Subtype Macrophages.

Calreticulin (CALR) has anti-tumor effects by increasing dendritic cell maturation and tumor antigen presentation. However, whether CALR affects macrophages and modulates progression of acute respiratory distress syndrome/acute lung injury (ARDS/ALI) remains unknown. In this study, we discovered that CALR protein was highly expressed in the mice with LPS-induced ALI and CALR expression level was positively correlated to the severity of ALI. Commercial anti-CALR antibody (aCALR) can neutralize recombinant CALR (rCALR) and suppress the expression of TNF-alpha and IL-6 in the rCALR-treated macrophages. Blocking CALR activity by intraperitoneal (i.p.) administration of aCALR significantly suppressed ALI, accompanied with lower total cell counts, neutrophil and T cell infiltration in bronchoalveolar lavage (BAL) and lung tissues. The expression of CXCL15, IL-6, IL-1beta, TNF-alpha, and CALR were significantly reduced, in association with more polarization of Siglec F+CD206+M2 subtype macrophages in the aCALR-treated mice. Pre-depletion of circulating monocytes did not abolish the aCALR-mediated suppression of ALI. Further analysis in bone marrow-derived macrophages (BMDMs) showed that aCALR suppressed the expression of CD80, IL-6, IL-1beta, IL-18, NLRP3, and p-p38 MAPK; but enhanced the expression of CD206 and IL-10. In addition, we observed more expression and phosphorylation of STAT6 in the aCALR-treated BMDM. Lack of STAT6 resulted in comparable and slightly higher expression of CALR, TNF-alpha and IL-6 in the aCALR-treated STAT6-/- BMDMs than the untreated cells. Therefore, we conclude that CALR is a novel biomarker in the evaluation of ALI. Blocking CALR activity by aCALR effectively suppressed ALI independent of circulating monocytes. Siglec F+CD206+M2 subtype macrophages and p38 MAPK/STAT6 signaling pathway played important role in the immune regulation of aCALR. Blocking CALR activity is a promising therapeutic approach in the treatment of ARDS/ALI.

Value in application of lung ultrasound in diagnosis of pulmonary disease and in lung-protective ventilation strategy

Lung ultrasound(LUS) has been widely used in the diagnosis of pulmonary diseases. However, the role of LUS in lung-protective ventilation strategy of the diagnosis and treatment in patients with pulmonary complications combined with acute respiratory distress syndrome/acute lung injury(ARDS/ALI) is still not clear. This review presents the research advances of diagnosis and therapy of pulmonary diseases as well as value of the LUS in lung-protective ventilation strategy in recent years. Through further investigation, the significance of clinical application of LUS will be confirmed. Application of LUS in the lung-protection ventilation strategy reduces the incidence of postoperative pulmonary complications and mortality and improves the prognosis of patients. Key words: Lung; Ultrasoud; Disease diagnosis; Lung-protective ventilation strategy; Acute respiratory distress syndrome; Acute lung injury

The Development of Serum Amyloid P as a Possible Therapeutic.

Pentraxins such as serum amyloid P (SAP; also known as PTX2) regulate several aspects of the innate immune system. SAP inhibits the differentiation of monocyte-derived fibroblast-like cells called fibrocytes, promotes the formation of immuno-regulatory macrophages, and inhibits neutrophil adhesion to extracellular matrix proteins. In this minireview, we describe how these effects of SAP have led to its possible use as a therapeutic, and how modulating SAP effects might be used for other therapeutics. Fibrosing diseases such as pulmonary fibrosis, cardiac fibrosis, liver fibrosis, and renal fibrosis are associated with 30–45% of deaths in the US. Fibrosis involves both fibrocyte differentiation and profibrotic macrophage differentiation, and possibly because SAP inhibits both of these processes, in 9 different animal models, SAP inhibited fibrosis. In Phase 1B and Phase 2 clinical trials, SAP injections reduced the decline in lung function in pulmonary fibrosis patients, and in a small Phase 2 trial SAP injections reduced fibrosis in myelofibrosis patients. Acute respiratory distress syndrome/ acute lung injury (ARDS/ALI) involves the accumulation of neutrophils in the lungs, and possibly because SAP inhibits neutrophil adhesion, SAP injections reduced the severity of ARDS in an animal model. Conversely, depleting SAP is a potential therapeutic for amyloidosis, topically removing SAP from wound fluid speeds wound healing in animal models, and blocking SAP binding to one of its receptors makes cultured macrophages more aggressive toward tuberculosis bacteria. These results suggest that modulating pentraxin signaling might be useful for a variety of diseases.

Acute respiratory distress syndrome and acute lung injury in patients with vertebral column fracture(s) and spinal cord injury: a nationwide inpatient sample study

Retrospective Nationwide Inpatient Sample (NIS) study. To determine national trends in prevalence, risk factors and mortality for vertebral column fracture (VCF) and spinal cord injury (SCI) patients with and without acute respiratory distress syndrome/acute lung injury (ARDS/ALI). United States of America, 1988 to 2008. The NIS was utilized to select 284 612 admissions for VCF with and without acute SCI from 1988 to 2008 based on ICD-9-CM. The data were stratified for in-hospital complications of ARDS/ALI. Patients with SCI were more likely to develop ARDS/ALI compared with those without (odds ratio (OR): 4.9, 95% confidence interval (CI) 4.7-5.2, P<0.001). Compared with patients with lumbar fractures, those with cervical, thoracic and sacral fractures were more likely to develop ARDS/ALI (P<0.001). ARDS/ALI was statistically more prevalent (P<0.01) in VCF/SCI patients with epilepsy, sepsis, cardiac arrest, congestive heart failure (CHF), hypertension, chronic obstructive pulmonary disease and metabolic disorders. Patients with female gender, surgery at rural practice setting, and coronary artery disease and diabetes were less likely to develop ARDS/ALI (P<0.001). VCF/SCI patients who developed ARDS/ALI were more likely to die in-hospital than those without ARDS/ALI (OR 6.5, 95% CI 6.0-7.1, P<0.001). Predictors of in-hospital mortality after VCF/SCI include: older age, male sex, epilepsy, sepsis, hypertension, CHF, chronic obstructive pulmonary disease and liver disease. Patients who developed ARDS/ALI stayed a mean of 25 hospital days (30-440 days) while patients without ARDS/ALI stayed a mean of 6 days (7-868 days, P<0.001). Our analysis demonstrates that SCI patients are more at risk for ARDS/ALI, which carries a significantly higher risk of mortality.

Local pulmonary administration of factor VIIa (rFVIIa) in diffuse alveolar hemorrhage (DAH) &amp;ndash; a review of a new treatment paradigm

BackgroundDiffuse alveolar hemorrhage (DAH) is a clinical syndrome with typical symptoms dyspnea and hemoptysis. DAH is a complication of specific diseases, in some cases with acute catastrophic hemoptysis, while other patients present low grade alveolar bleeding with a need of chronic transfusion as in pulmonary hemosiderosis.MethodsCurrent literature in the PubMed database and other sources was reviewed in order to evaluate the current treatment recommendations, efficacy of this treatment, and finally the risk of complications after off-label use of rFVIIa in respect to DAH.Objectives(i) To elucidate the clinical aspects of alveolar hemorrhage, (ii) to develop a simple diagnostic algorithm in order to separate DAH from other important pulmonary diseases with similar clinical picture and comparably high mortality. Such an algorithm has important therapeutic consequences because these diseases: acute lung injury (ALI), acute respiratory distress syndrome (ARDS) and bronchiolitis obliterans organizing pneumonia (BOOP) have different therapies, (iii) to evaluate and discuss whether local pulmonary administration may improve outcome and reduce mortality in DAH, and (iv) to suggest a treatment schedule.ResultsHitherto the diagnosis and treatment of DAH has been based on anecdotal reports. The treatment has relied on different unspecific treatment modalities based on a mixture of treatment of the underlying disease and treatment without evidence targeted to stop the alveolar bleeding. However, recently a number of publications have advocated the use of intrapulmonary rFVIIa. Even in severe bleeding DAH has been shown to respond promptly without thromboembolic complication when FVIIa was administered locally via the air side, because the FVIIa does not penetrate the alveolo-capillary membrane to the blood-side. The incidence of DAH (in the US and Europe is 100,000–150,000, and 50,000 patients annually are at risk of developing DAH following hematopoietic stem cell transplant (HSCT) and autoimmune diseases. Finally 50,000–100,000 patients may be falsely categorized as having acute respiratory distress syndrome/acute lung injury (ARDS/ALI) because DAH and ARDS cannot be separated clinically. A new treatment paradigm of DAH is proposed as no other intervention has been able to ensure pulmonary hemostasis in DAH. The diagnosis of DAH is simple, a series of broncho-alveolar washes which become increasingly bloody. This test should be performed in all patients with pulmonary opacities in order to separate ARDS/ALI from DAH. FVIIa administrated via pulmonary route is “drug of choice”, because it stops bleeding in the life-threatening syndrome DAH. Hemostasis is obtained after only one to two small doses of FVIIa (50 μg/kg body weight per dose) and after hemostasis the oxygen transport quickly improves.ConclusionIntrapulmonary administration of rFVIIa is recommended as the treatment of choice for DAH and blast lung injury (BLI) because the treatment has been shown to be successful and uncomplicated in spite of the fact that only a small series of DAH has been documented.

Influence of Low Tidal Volume Ventilation on Time to Extubation in Cardiac Surgical Patients

Low tidal volumes are clearly beneficial for patients with established acute respiratory distress syndrome/acute lung injury (ARDS/ALI).1–3 However, the optimal mechanical ventilation of patients at risk of ARDS/ALI remains unclear. In theory, lung overdistention could contribute to lung injury among predisposed individuals, leading to prolongation of mechanical ventilation. Gajic et al.4 conducted a retrospective analysis of patients who did not have ARDS when mechanical ventilation was initiated. They observed that high tidal volume was an independent risk factor for ALI among patients with relatively normal gas exchange. The authors4 concluded that strong consideration should be given to limiting large tidal volume, not only among patients with established ALI, but also for at-risk patients. Subsequent retrospective analyses have confirmed these findings.5,6 However, other researchers7 have suggested that low tidal volume may be unnecessary in non-ALI cases and that it may lead unnecessarily to patient discomfort, increased work during breathing, high sedation requirements, autopositive end-expiratory pressure (PEEP; high respiratory rate), hypercapnia (low respiratory rate), and atelectasis. Thus, despite biologic plausibility and considerable retrospective data to support limiting tidal volume in all ventilated patients, equipoise remains regarding optimal tidal volume in non-ALI patients. Although various groups of surgical patients, but especially cardiac surgical patients, have been observed,8–20 these investigations have focused primarily on surrogate outcomes measures, leaving a lack of clarity regarding optimal perioperative ventilator strategy. Therefore, we performed a randomized controlled trial comparing ventilation with 6 versus 10 ml/kg tidal volume for patients undergoing elective cardiac surgery. We hypothesized that using a low tidal volume ventilator strategy would reduce ventilator-associated lung injury and that this improvement would reduce time to extubation.

Bedside Ultrasound Assessment of Positive End-Expiratory Pressure–induced Lung Recruitment

In the critically ill patients, lung ultrasound (LUS) is increasingly being used at the bedside for assessing alveolar-interstitial syndrome, lung consolidation, pneumonia, pneumothorax, and pleural effusion. It could be an easily repeatable noninvasive tool for assessing lung recruitment. Our goal was to compare the pressure-volume (PV) curve method with LUS for assessing positive end-expiratory pressure (PEEP)-induced lung recruitment in patients with acute respiratory distress syndrome/acute lung injury (ARDS/ALI). Thirty patients with ARDS and 10 patients with ALI were prospectively studied. PV curves and LUS were performed in PEEP 0 and PEEP 15 cm H₂O₂. PEEP-induced lung recruitment was measured using the PV curve method. Four LUS entities were defined: consolidation; multiple, irregularly spaced B lines; multiple coalescent B lines; and normal aeration. For each of the 12 lung regions examined, PEEP-induced ultrasound changes were measured, and an ultrasound reaeration score was calculated. A highly significant correlation was found between PEEP-induced lung recruitment measured by PV curves and ultrasound reaeration score (Rho = 0.88; P < 0.0001). An ultrasound reaeration score of +8 or higher was associated with a PEEP-induced lung recruitment greater than 600 ml. An ultrasound lung reaeration score of +4 or less was associated with a PEEP-induced lung recruitment ranging from 75 to 450 ml. A statistically significant correlation was found between LUS reaeration score and PEEP-induced increase in Pa(O₂) (Rho = 0.63; P < 0.05). PEEP-induced lung recruitment can be adequately estimated with bedside LUS. Because LUS cannot assess PEEP-induced lung hyperinflation, it should not be the sole method for PEEP titration.

Less Is More: Improved Outcomes in Surgical Patients with Conservative Fluid Administration and Central Venous Catheter Monitoring

The ARDS Clinical Trials Network Fluid and Catheter Treatment Trial (FACTT) addressed fluid management and central monitoring of patients with acute respiratory distress syndrome/acute lung injury (ARDS/ALI). Because surgical patients may have been fundamentally different from the overall FACTT cohort, we set out to separately analyze the surgery patients in the trial. We performed a posthoc, surgical subgroup analysis of 1,000 patients enrolled in the FACTT. Patients were randomized using a 2x2 factorial design comparing a conservative (CON) versus a liberal (LIB) strategy of fluid management and the use of a pulmonary artery catheter (PAC) or a central venous catheter (CVC). The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days, ICU-free days, and dialysis-free days until hospital discharge up to day 90. We defined surgical patients as those admitted to a surgical ICU, burn ICU, or cardiac surgical ICU; trauma patients; or those with an APACHE III surgical admission type. There were 244 surgical patients. Risk of death within 60 days of randomization did not vary with catheter or fluid management, and a corresponding lack of effect was evident with regard to dialysis-free days. Ventilator-free days were increased in the fluid-conservative group (LIB, 13+/-1 days; CON, 15+/-1 days; p=0.04) at 28 days. CVC patients had more ventilator-free days at 28 and 90 days (28 days: CVC, 16+/-1 days; PAC, 13+/-1 days; p=0.03; 90 days: CVC, 64+/-3 days; PAC, 57+/-4 days; p=0.03). CVC patients had more ICU-free days at 90 days (90 days: CVC, 63+/-3 days; PAC, 55+/-3 days; p=0.04). The risk of death did not vary with fluid management or catheter. A conservative fluid-administration strategy and central venous catheter monitoring resulted in more ventilator-free and ICU-free days in surgical patients with acute lung injury, and conservative fluid administration did not result in more renal failure.

Osteopontin is Strongly Expressed by Alveolar Macrophages in the Lungs of Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) is characterized by an intense inflammatory response in the lung parenchyma. Recent studies suggest that excessive nitric oxide (NO) production mediated by inducible NO synthase (iNOS) in macrophages is partially involved in mediating acute lung injury in ARDS. On the other hand, osteopontin (OPN) is a cytokine which is capable of inhibiting NO production by suppressing iNOS mRNA expression in macrophages. In this study, we investigated the expression of OPN in the lungs of 10 patients with ARDS. In most patients, OPN is strongly expressed on alveolar macrophages. In addition, we produced a murine model for ARDS by intratracheal administration of lipopolysaccharide and investigated the expression of endogenous OPN and iNOS in the lungs of ARDS mice. Immunostaining demonstrated that in vivo OPN protein was coinduced with iNOS protein predominantly in the accumulating alveolar macrophages. OPN mRNA expression was also coinduced with iNOS mRNA, but was induced more slowly than iNOS mRNA in the lungs of ARDS mice. These results suggested that OPN, which may reduce NO production of macrophages by inhibiting iNOS expression, is significantly induced and expressed on alveolar macrophages in the lungs of ARDS. It is possible that OPN is partially involved in playing a protective role against excessive production of NO in ARDS.

Inhalation/intravenous recombinant tissue plasminogen activator and inhaled heparin in a patient with acute respiratory distress syndrome

Recent studies have demonstrated that lung fibrin deposits are associated with evolution of acute respiratory distress syndrome (ARDS). A young woman with ARDS resistant to conventional treatment was treated with ultrasonic nebulized rt-PA (30 mg) and intravenous rt-PA (20 mg) over 2 h followed by continuous treatment with ultrasonic nebulized unfractionated heparin (15 000 IU/day). The pulmonary gas exchange of the patient improved significantly and the condition of the patient stabilized during the hours following the fibrinolytic treatment. The potential use of nebulized thrombolytics for local treatment of ARDS is discussed, and we conclude that combined nebulized and intravenous therapy with thrombolytics may improve physiologic derangements associated with acute lung injury in ARDS.