Management Of Acute Lung Injury Research Articles

Mesenchymal stem cells shift the pro-inflammatory phenotype of neutrophils to ameliorate acute lung injury

BackgroundMesenchymal stem cell (MSC) treatment plays a major role in the management of acute lung injury (ALI), and neutrophils are the initial line of defense against ALI. However, the effect of MSCs on neutrophils in ALI remains mostly unknown.MethodsWe investigated the characteristics of neutrophils in lung tissue of ALI mice induced by lipopolysaccharide after treatment with MSCs using single-cell RNA sequencing. Neutrophils separated from lung tissue in ALI were co-cultured with MSCs, and then samples were collected for reverse transcription-polymerase chain reaction and flow cytometry.ResultsDuring inflammation, six clusters of neutrophils were identified, annotated as activated, aged, and circulatory neutrophils. Activated neutrophils had higher chemotaxis, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase scores than aged neutrophils. Circulatory neutrophils occurred mainly in healthy tissue and were characterized by higher expression of Cxcr2 and Sell. Activated neutrophils tended to exhibit higher expression of Cxcl10 and Cd47, and lower expression of Cd24a, while aged neutrophils expressed a lower level of Cd47 and higher level of Cd24a. MSC treatment shifted activated neutrophils toward an aged neutrophil phenotype by upregulating the expression of CD24, thereby inhibiting inflammation by reducing chemotaxis, ROS production, and NADPH oxidase.ConclusionWe identified the immunosuppressive effects of MSCs on the subtype distribution of neutrophils and provided new insight into the therapeutic mechanism of MSC treatment in ALI.

Factor H preserves alternative complement function during ARDS, linked to improved survival.

Effective regulation of complement activation may be crucial to preserving complement function during acute respiratory distress syndrome (ARDS). Factor H is the primary negative regulator of the alternative pathway of complement. We hypothesised that preserved factor H levels are associated with decreased complement activation and reduced mortality during ARDS. Total alternative pathway function was measured by serum haemolytic assay (AH50) using available samples from the ARDSnet Lisofylline and Respiratory Management of Acute Lung Injury (LARMA) trial (n=218). Factor B and factor H levels were quantified using ELISA using samples from the ARDSnet LARMA and Statins for Acutely Injured Lungs from Sepsis (SAILS) (n=224) trials. Meta-analyses included previously quantified AH50, factor B and factor H values from an observational registry (Acute Lung Injury Registry and Biospecimen Repository (ALIR)). Complement C3, and complement activation products C3a and Ba plasma levels were measured in SAILS. AH50 greater than the median was associated with reduced mortality in meta-analysis of LARMA and ALIR (hazard ratio (HR) 0.66, 95% CI 0.45-0.96). In contrast, patients in the lowest AH50 quartile demonstrated relative deficiency of both factor B and factor H. Relative deficiency of factor B (HR 1.99, 95% CI 1.44-2.75) or factor H (HR 1.52, 95% CI 1.09-2.11) was associated with increased mortality in meta-analysis of LARMA, SAILS and ALIR. Relative factor H deficiency was associated with increased factor consumption, as evidenced by lower factor B and C3 levels and Ba:B and C3a:C3 ratios. Higher factor H levels associated with lower inflammatory markers. Relative factor H deficiency, higher Ba:B and C3a:C3 ratios and lower factor B and C3 levels suggest a subset of ARDS with complement factor exhaustion, impaired alternative pathway function, and increased mortality, that may be amenable to therapeutic targeting.

First Evidence of the Protective Effects of 2-Pentadecyl-2-Oxazoline (PEA-OXA) in In Vitro Models of Acute Lung Injury

Acute respiratory distress syndrome (ARDS) is a serious inflammatory lung disorder and a complication of SARS-CoV-2 infection. In patients with severe SARS-CoV-2 infection, the transition to ARDS is principally due to the occurrence of a cytokine storm and an exacerbated inflammatory response. The effectiveness of ultra-micronized palmitoylethanolamide (PEA-um) during the earliest stage of COVID-19 has already been suggested. In this study, we evaluated its protective effects as well as the effectiveness of its congener, 2-pentadecyl-2-oxazoline (PEA-OXA), using in vitro models of acute lung injury. In detail, human lung epithelial cells (A549) activated by polyinosinic-polycytidylic acid (poly-(I:C)) or Transforming Growth Factor-beta (TGF-β) were treated with PEA-OXA or PEA. The release of IL-6 and the appearance of Epithelial-Mesenchymal Transition (EMT) were measured by ELISA and immunofluorescence assays, respectively. A possible mechanism of action for PEA-OXA and PEA was also investigated. Our results showed that both PEA-OXA and PEA were able to counteract poly-(I:C)-induced IL-6 release, as well as to revert TGF-β-induced EMT. In addition, PEA was able to produce an "entourage" effect on the levels of the two endocannabinoids AEA and 2-AG, while PEA-OXA only increased PEA endogenous levels, in poly-(I:C)-stimulated A549 cells. These results evidence for the first time the superiority of PEA-OXA over PEA in exerting protective effects and point to PEA-OXA as a new promising candidate in the management of acute lung injury.

Mesenchymal Stem Cell-Derived Extracellular Vesicles in the Management of COVID19-Associated Lung Injury: A Review on Publications, Clinical Trials and Patent Landscape.

The unprecedented COVID-19 pandemic situation forced the scientific community to explore all the possibilities from various fields, and so far we have seen a lot of surprises, eureka moments and disappointments. One of the approaches from the cellular therapists was exploiting the immunomodulatory and regenerative potential of mesenchymal stromal cells (MSCs), more so of MSC-derived extracellular vesicles (EVs)—particularly exosomes, in order to alleviate the cytokine storm and regenerate the damaged lung tissues. Unlike MSCs, the EVs are easier to store, deliver, and are previously shown to be as effective as MSCs, yet less immunogenic. These features attracted the attention of many and thus led to a tremendous increase in publications, clinical trials and patent applications. This review presents the current landscape of the field and highlights some interesting findings on MSC-derived EVs in the context of COVID-19, including in silico, in vitro, in vivo and case reports. The data strongly suggests the potential of MSC-derived EVs as a therapeutic regime for the management of acute lung injury and associated complications in COVID-19 and beyond.Graphical abstract

Fluid restriction versus conventional fluid administration in acute lung injury patients (Comparative study between different strategies of fluid administration in acute lung injury patients)

Abstract Background Acute lung injury and ARDS are major causes of morbidity and mortality all over the world. Major steps of understanding the pathophysiology, causes, diagnosis and treatment of this syndrome were taken in last twenty year. Diagnosis of this condition remains underestimated by physicians particularly mild form of this syndrome specially in developing world in which presence of investigations and well trained physicians is not adequate. Objective To compare between the outcomes of fluid administration strategies in the form of restricted or conventional fluid administration that affect oxygenation, weaning of mechanical ventilation and free days of icu admission in acute lung injury patients and its severe form ARDS. To detect the optimal strategy of fluid administration which decrease morbidity and mortality. Patients and Methods Type of Study: Prospective study. Study Setting: The study will be conducted in the ICU units at Ain-Shams University Hospitals and Ahmed Maher Teaching Hospital. Study Period: Four months from date of approval of the protocol. 90 adult patients- divided into three groups each group include 30 patients- (fulfilling inclusion criteria) admitted in the ICU units at Ain Shams University Hospitals and Ahmed Maher Teaching Hospital were included. Results Based on more than one point of view; underlying cause of ARDS palys major role in predicting these unpredictable results of this study in haemodynamically unstable patients. There are many factors, rather than hypoxemia, that affect organ outcomes (including respiratory system itself) in haemodynamically unstable patients which may caused by septic shock and other types of shock. Conclusion This small trial evoked new questions more than answering traditional ones about fluid management of acute lung injury and ARDS. Firstly; the accurate method to assess and guide fluid therapy in ARDS should be on top of searching priorities. Although using central venous pressure to guide fluid therapy could theoretically results in outcome improvement, but according to its many limitations and poor relation to volume status, its using in that issue is questionable. Secondly; establishing one fluid management strategy to all patients with ARDS seems to be not accurate. Unpredictable results on outcomes in ARDS patients receiving fluids particularly in those were haemodynamically unstable drive us to seek for new classification of ARDS patients based on underlying cause, haemodynamic stability and other elements that responsible for organ failure rather than volume status. However; this small trial suggests conservative fluid strategy in acute lung injury patients which are haemodynamically stable. And using of both conservative and liberal fluid administration strategies wisely in those patients which are haemodynamically unstable to reach the optimal intravascular volume– pressure with the best risk–benefit ratio.

Management of Acute Lung Injury: Palmitoylethanolamide as a New Approach.

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are common and devastating clinical disorders with high mortality and no specific therapy. Lipopolysaccharide (LPS) is usually used intratracheally to induce ALI in mice. The aim of this study was to examine the effects of an ultramicronized preparation of palmitoylethanolamide (um-PEA) in mice subjected to LPS-induced ALI. Histopathological analysis reveals that um-PEA reduced alteration in lung after LPS intratracheal administration. Besides, um-PEA decreased wet/dry weight ratio and myeloperoxidase, a marker of neutrophils infiltration, macrophages and total immune cells number and mast cells degranulation in lung. Moreover, um-PEA could also decrease cytokines release of interleukin (IL)-6, interleukin (IL)-1β, tumor necrosis factor (TNF)-α and interleukin (IL)-18. Furthermore, um-PEA significantly inhibited the phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation in ALI, and at the same time decreased extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38/MAPK) expression, that was increased after LPS administration. Our study suggested that um-PEA contrasted LPS-induced ALI, exerting its potential role as an adjuvant anti-inflammatory therapeutic for treating lung injury, maybe also by p38/NF-κB pathway.

A glimpse at growth hormone–releasing hormone cosmos

Growth hormone-releasing hormone is a hypothalamic neuropeptide, which regulates the secretion of growth hormone by the anterior pituitary gland. Recent evidence suggest that it exerts growth factor activities in a diverse variety of in vivo and in vitro experimental malignancies, which are counteracted by growth hormone-releasing hormone antagonists. Those peptides support lung endothelial barrier integrity by suppressing major inflammatory pathways and by inducing the endothelial defender P53. The present effort provides information regarding the effects of growth hormone-releasing hormone in the regulation of P53 and the unfolded protein response. Furthermore, it suggests the possible application of growth hormone-releasing hormone antagonists towards the management of acute lung injury, including the lethal acute respiratory distress syndrome.

IL-16/miR-125a axis controls neutrophil recruitment in pristane-induced lung inflammation.

Severe lung inflammation and alveolar hemorrhage can be life-threatening in systemic lupus erythematosus (SLE) patients if not treated early and aggressively. Neutrophil influx is the driver key of this pathology, but little is known regarding the molecular events regulating this recruitment. Here, we uncover a role for IL-16/mir-125a in this pathology and show not only that IL-16 is a target for miR-125a but that reduced miR-125a expression in SLE patients associates with lung involvement. Furthermore, in the pristane model of acute "SLE-like" lung inflammation and alveolar hemorrhage, we observed reduced pulmonary miR-125a and enhanced IL-16 expression. Neutrophil infiltration was markedly reduced in the peritoneal lavage of pristane-treated IL-16-deficient mice and elevated following i.n. delivery of IL-16. Moreover, a miR-125a mimic reduced pristane-induced IL-16 expression and neutrophil recruitment and rescued lung pathology. Mechanistically, IL-16 acts directly on the pulmonary epithelium and markedly enhances neutrophil chemoattractant expression both in vitro and in vivo, while the miR-125a mimic can prevent this. Our results reveal a role for miR-125a/IL-16 in regulating lung inflammation and suggest this axis may be a therapeutic target for management of acute lung injury in SLE.

Prone Positioning Is a Safe and Effective Method in the Management of Acute Lung Injury after Cardiac Surgery

Prone Positioning Is a Safe and Effective Method in the Management of Acute Lung Injury after Cardiac Surgery

Targeting the Canonical Nuclear Factor-κB Pathway with a High-Potency IKK2 Inhibitor Improves Outcomes in a Mouse Model of Idiopathic Pneumonia Syndrome

Idiopathic pneumonia syndrome (IPS) is a noninfectious inflammatory disorder of the lungs that occurs most often after fully myeloablative allogeneic hematopoietic stem cell transplantation (HSCT). IPS can be severe and is associated with high 1-year mortality rates despite existing therapies. The canonical nuclear factor-(NF) κB signaling pathway has previously been linked to several inflammatory disorders of the lung, including asthma and lung allograft rejection. It has never been specifically targeted as a novel IPS treatment approach, however. Here, we report that the IκB kinase 2 (IKK2) antagonist BAY 65-5811 or “compound A,” a highly potent and specific inhibitor of the NF-κB pathway, was able to improve median survival times and recipient oxygenation in a well-described mouse model of IPS. Compound A impaired the production of the proinflammatory chemokines CCL2 and CCL5 within the host lung after transplantation. This resulted in significantly lower numbers of donor lung infiltrating CD4+ and CD8+ T cells and reduced pulmonary inflammatory cytokine production after allograft. Compound A's beneficial effects appeared to be specific for limiting pulmonary injury, as the drug was unable to improve outcomes in a B6 into B6D2 haplotype-matched murine HSCT model in which recipient mice succumb to lethal acute graft-versus-host disease of the gastrointestinal tract. Collectively, our data suggest that the targeting of the canonical NF-κB pathway with a small molecule IKK2 antagonist may represent an effective and novel therapy for the specific management of acute lung injury that can occur after allogeneic HSCT.

Protective effect of ulinastatin in patients with non-small cell lung cancer after radiation therapy: a randomized, placebo-controlled study.

Radiation-induced lung injury (RILI) is a frequent, sometimes life-threatening complication of radiation therapy for the treatment of lung cancer. The anti-inflammatory role of ulinastatin has been well documented, and the potential application of ulinastatin in management of acute lung injury has been suggested in multiple animal studies. In this article, we described a double-blind, randomized, placebo-controlled study in patients with non-small cell lung cancer. A total of 120 patients were randomized into two groups: the trial group was treated with ulinastatin for 3days prior to and for the first 7days of radiation therapy and the control group was treated with placebo for 10days following the same schedule. The results from follow-up studies showed that the incidence and grade of RILI were significantly lower in the trial group than in the control group. Reduction in pulmonary function from baseline was significantly smaller in the trial group than that in the control group. Production of serum TGF-β1, TNF-α and IL-6 decreased significantly in the trial group promptly following radiation therapy. However, no difference in survival or tumour response rate was found between the two groups. The results indicated that ulinastatin exerted a protective effect on radiation-induced lung injury. Treatment with ulinastatin could be an effective management strategy and greatly improve the clinical efficacy of radiation therapy for patients with lung cancer.

TRPV4: an exciting new target to promote alveolocapillary barrier function.

Transient receptor potential (TRP) channels are emerging as important players and drug targets in respiratory disease. Amongst the vanilloid-type TRP channels (which includes the six members of the TRPV family), target diseases include cough, asthma, cancer, and more recently, pulmonary edema associated with acute respiratory distress syndrome. Here, we critically evaluate a recent report that addresses TRPV4 as a candidate target for the management of acute lung injury that develops as a consequence of aspiration of gastric contents, or acute chlorine gas exposure. By use of two new TRPV4 inhibitors (GSK2220691 or GSK2337429A) and a trpv4(-/-) mouse strain, TRPV4 was implicated as a key mediator of pulmonary inflammation after direct chemical insult. Additionally, applied therapeutically, TRPV4 inhibitors exhibited vasculoprotective effects after chlorine gas exposure, inhibiting vascular leakage, and improving blood oxygenation. These observations underscore TRPV4 channels as candidate therapeutic targets in the management of lung injury, with the added need to balance these against the potential drawbacks of TRPV4 inhibition, such as the danger of limiting the immune response in settings of pathogen-provoked injury.

Tidal volume and plateau pressure use for acute lung injury from 2000 to present: a systematic literature review.

Since publication of the Respiratory Management of Acute Lung Injury and Acute Respiratory Distress Syndrome (ARMA) trial in 2000, use of tidal volume (VT) less than or equal to 6 mL/kg predicted body weight with corresponding plateau airway pressures (PPlat) less than or equal to 30 cm H2O has been advocated for acute lung injury. However, compliance with these recommendations is unknown. We therefore investigated VT (mL/kg predicted body weight) and PPlat (cm H2O) practices reported in studies of acute lung injury since ARMA using a systematic literature review (i.e., not a meta-analysis). PubMed, Scopus, and EMBASE. Randomized controlled trials and nonrandomized studies enrolling patients with acute lung injury from May 2000 to June 2013 and reporting VT. Whether the study was a randomized controlled trial or a nonrandomized study and performed or not at an Acute Respiratory Distress Syndrome Network center; in randomized controlled trials, the pre- and postrandomization VT (mL/kg predicted body weight) and PPlat (cm H2O) and whether a VT protocol was used postrandomization; in nonrandomized studies, baseline VT and PPlat. Twenty-two randomized controlled trials and 71 nonrandomized studies were included. Since 2000 at acute respiratory distress syndrome Network centers, routine VT was similar comparing randomized controlled trials and nonrandomized studies (p = 0.25) and unchanged over time (p = 0.75) with a mean value of 6.81 (95% CI, 6.45, 7.18). At non-acute respiratory distress syndrome Network centers, routine VT was also similar when comparing randomized controlled trials and nonrandomized studies (p = 0.71), but decreased (p = 0.001); the most recent estimate for it was 6.77 (6.22, 7.32). All VT estimates were significantly greater than 6 (p ≤ 0.02). In randomized controlled trials employing VT protocols, routine VT was reduced in both acute respiratory distress syndrome Network (n = 4) and non-acute respiratory distress syndrome Network (n = 11) trials (p ≤ 0.01 for both), but even postrandomization was greater than 6 (6.47 [6.29, 6.65] and 6.80 [6.42, 7.17], respectively; p ≤ 0.0001 for both). In 59 studies providing data, routine PPlat, averaged across acute respiratory distress syndrome Network or non-acute respiratory distress syndrome Network centers, was significantly less than 30 (p ≤ 0.02). For clinicians treating acute lung injury since 2000, achieving VT less than or equal to 6 mL/kg predicted body weight may not have been as attainable or important as PPlat less than or equal to 30 cm H2O. If so, there may be equipoise to test if VT less than or equal to 6 mL/kg predicted body weight are necessary to improve acute lung injury outcome.

S94 Tumour Necrosis Factor receptor 1 inhibition using a novel inhaled human antibody reduces inflammation in a human model of lung injury induced by inhaled lipopolysaccharide; a randomised placebo-controlled clinical trial

Introduction and ObjectivesTumour Necrosis Factor receptor 1 (TNFR1) transduces the pro-inflammatory activity of TNF-α, whereas signalling through TNFR2 may contribute to tissue repair. Attenuation of TNFR1 signalling, whilst simultaneously preserving...

Management of acute lung injury and acute respiratory distress syndrome in infants

Acute lung injury and acute respiratory distress (ALI/ARDS) is a clinical syndrome caused primarily by increased permeability to proteins across the endothelial and epithelial barriers of the lungs. It is characterized as restrictive disease with reduced lung compliance caused by loss of surfactant function, atelectatic lung regions and accumulation of interstitial/alveolar plasma leakage. Patients usually develop acute respiratory failure rapidly because of arterial hypoxemia as well as impaired carbon dioxide excretion and elevated work of breathing. The American–European Consensus Conference (AECC) in 1994 defined ARDS as respiratory failure of acute onset with a PaO2/FiO2 ratio ≤200 mm Hg (regardless of the level of positive end expiratory pressure, PEEP) and bilateral infiltrates on a frontal chest radiograph. ALI is defined identically except for a higher PaO2/FiO2 limit of <300 mm Hg. A large prospective trial from Spain demonstrated that 1.4% of all patients admitted to the paediatric intensive care unit and 8.3% of all those mechanically ventilated met ARDS criteria [1]. Overall mortality in children suffering from ALI/ARDS ranges from 18 to 27%, but increases to 29–50% when considering only the ARDS group and is only 3–11% in those who do not develop ARDS [2]. It is essential, however, to distinguish between ALI/ARDS associated with direct pulmonary causes compared to systemic (indirect, extra-pulmonary) causes. In infants, as well as in children and adults, the most frequent direct cause of either ALI or ARDS is viral or bacterial pneumonia, followed by aspiration (e.g., gastric aspiration, meconium aspiration in newborns) and, less frequently, near-drowning and inhalation of toxicants. Indirect (systemic) causes of ALI/ARDS are primarily systemic infections followed by burn injury, hypovolemic shock, generalized trauma, multiple transfusions and other primary extra-pulmonary injuries. Indirect forms of ALI/ARDS have substantial multi-organ pathologies that

Corrigendum

Ajay Dharia and Carolyn S. Calfee, Updates in the Management of Acute Lung Injury, 2012; 3 (6), 287-292 original doi ( 10.1177/1944451612466107 ). In the November 2012 issue of ICU Director, for the article listed above, the authors wish to correct an error in the references for Tables 1 and 2. The incorrect citations are found in the table legend. For Table 1 the legend should read ‘Adapted from Bernard et al.’ (ref # 6) and in Table 2 should read ‘Adapted from ARDS Definition Task Force et al.’ (ref # 7).

Lung ventilation strategies and regional lung inflammation

Protective mechanical ventilation is currently accepted as a key strategy for the management of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome. The study by de Prost and colleagues in the current issue of Critical Care provides new insights into the impact of ventilation strategies on pulmonary function, gas exchange, and regional cellular metabolic activity during early ALI in sheep. The group reports that a protective ventilation strategy may attenuate neutrophil activation in dependent lung regions during early experimental ALI. This is an innovative report that provides the basis for further study.

Updates in the Management of Acute Lung Injury

Acute lung injury (ALI) is commonly encountered in the ICU and is associated with significant mortality. The mainstay of therapy continues to be aggressive supportive care, including low tidal volume ventilation and fluid conservative strategies. Recent developments in the field of ALI include a proposal to modify the diagnostic criteria for ALI in the Berlin Definition and recent randomized controlled trials of the use of neuromuscular blockade, beta-agonists, and feeding strategies. The goal of this article is to review, summarize, and comment on these emerging data and offer practical recommendations for the evidence-based management of ALI.

Embracing Physical and Neuropsychological Dysfunction in Acute Lung Injury Survivors: The Time Has Come

Embracing Physical and Neuropsychological Dysfunction in Acute Lung Injury Survivors: The Time Has Come

Biomarkers of acute lung injury: worth their salt?

The validation of biomarkers has become a key goal of translational biomedical research. The purpose of this article is to discuss the role of biomarkers in the management of acute lung injury (ALI) and related research. Biomarkers should be sensitive and specific indicators of clinically important processes and should change in a relevant timeframe to affect recruitment to trials or clinical management. We do not believe that they necessarily need to reflect pathogenic processes. We critically examined current strategies used to identify biomarkers and which, owing to expedience, have been dominated by reanalysis of blood derived markers from large multicenter Phase 3 studies. Combining new and existing validated biomarkers with physiological and other data may add predictive power and facilitate the development of important aids to research and therapy.