Recent progress and prospects for anti-cytokine therapy in preclinical and clinical acute lung injury

Acute respiratory distress syndrome (ARDS) is a heterogeneous cause of respiratory failure that has a rapid onset, a high mortality rate, and for which there is no effective pharmacological treatment. Current evidence supports a critical role of excessive inflammation in ARDS, resulting in several cytokines, cytokine receptors, and proteins within their downstream signalling pathways being putative therapeutic targets. However, unsuccessful trials of anti-inflammatory drugs have thus far hindered progress in the field. In recent years, the prospects of precision medicine and therapeutic targeting of cytokines coevolving into effective treatments have gained notoriety. There is an optimistic and growing understanding of ARDS subphenotypes as well as advances in treatment strategies and clinical trial design. Furthermore, large trials of anti-cytokine drugs in patients with COVID-19 have provided an unprecedented amount of information that could pave the way for therapeutic breakthroughs. While current clinical and nonclinical ARDS research suggest relatively limited potential in monotherapy with anti-cytokine drugs, combination therapy has emerged as an appealing strategy and may provide new perspectives on finding safe and effective treatments. Accurate evaluation of these drugs, however, also relies on well-founded experimental research and the implementation of biomarker-guided stratification in future trials. In this review, we provide an overview of anti-cytokine therapy for acute lung injury and ARDS, highlighting the current preclinical and clinical evidence for targeting the main cytokines individually and the therapeutic prospects for combination therapy.     

Mechanical ventilation: lessons from the ARDSNet trial

The acute respiratory distress syndrome (ARDS) is an inflammatory disease of the lungs characterized clinically by bilateral pulmonary infiltrates, decreased pulmonary compliance and hypoxemia. Although supportive care for ARDS seems to have improved over the past few decades, few studies have shown that any treatment can decrease mortality for this deadly syndrome. In the 4 May 2000 issue of New England Journal of Medicine, the results of an NIH-sponsored trial were presented; they demonstrated that the use of a ventilatory strategy that minimizes ventilator-induced lung injury leads to a 22% decrease in mortality. The implications of this study with respect to clinical practice, further ARDS studies and clinical research in the critical care setting are discussed.     

Drugs to cure avian influenza infection – multiple ways to prevent cell death

New treatments and new drugs for avian influenza virus (AIV) infection are developed continually, but there are still high mortality rates. The main reason may be that not all cell death pathways induced by AIV were blocked by the current therapies. In this review, drugs for AIV and associated acute respiratory distress syndrome (ARDS) are summarized. The roles of antioxidant (vitamin C) and multiple immunomodulators (such as Celecoxib, Mesalazine and Eritoran) are discussed. The clinical care of ARDS may result in ischemia reperfusion injury to poorly ventilated alveolar cells. Cyclosporin A should effectively inhibit this kind of damages and, therefore, may be the key drug for the survival of patients with virus-induced ARDS. Treatment with protease inhibitor Ulinastatin could also protect lysosome integrity after the infection. Through these analyses, a large drug combination is proposed, which may hypothetically greatly reduce the mortality rate.     

Proteomic study of acute respiratory distress syndrome: current knowledge and implications for drug development

The acute respiratory distress syndrome (ARDS) is a common cause of acute respiratory failure, and is associated with substantial mortality and morbidity. Dozens of clinical trials targeting ARDS have failed, with no drug specifically targeting lung injury in widespread clinical use. Thus, the need for drug development in ARDS is great. Targeted proteomic studies in ARDS have identified many key pathways in the disease, including inflammation, epithelial injury, endothelial injury or activation, and disordered coagulation and repair. Recent studies reveal the potential for proteomic changes to identify novel subphenotypes of ARDS patients who may be most likely to respond to therapy and could thus be targeted for enrollment in clinical trials. Nontargeted studies of proteomics in ARDS are just beginning and have the potential to identify novel drug targets and key pathways in the disease. Proteomics will play an important role in phenotyping of patients and developing novel therapies for ARDS in the future.     

Current status and prospects of basic research and clinical application of mesenchymal stem cells in acute respiratory distress syndrome

Acute respiratory distress syndrome (ARDS) is a common and clinically devastating disease that causes respiratory failure. Morbidity and mortality of patients in intensive care units are stubbornly high, and various complications severely affect the quality of life of survivors. The pathophysiology of ARDS includes increased alveolar–capillary membrane permeability, an influx of protein-rich pulmonary edema fluid, and surfactant dysfunction leading to severe hypoxemia. At present, the main treatment for ARDS is mechanical treatment combined with diuretics to reduce pulmonary edema, which primarily improves symptoms, but the prognosis of patients with ARDS is still very poor. Mesenchymal stem cells (MSCs) are stromal cells that possess the capacity to self-renew and also exhibit multilineage differentiation. MSCs can be isolated from a variety of tissues, such as the umbilical cord, endometrial polyps, menstrual blood, bone marrow, and adipose tissues. Studies have confirmed the critical healing and immunomodulatory properties of MSCs in the treatment of a variety of diseases. Recently, the potential of stem cells in treating ARDS has been explored via basic research and clinical trials. The efficacy of MSCs has been shown in a variety of in vivo models of ARDS, reducing bacterial pneumonia and ischemia-reperfusion injury while promoting the repair of ventilator-induced lung injury. This article reviews the current basic research findings and clinical applications of MSCs in the treatment of ARDS in order to emphasize the clinical prospects of MSCs.     

急性肺损伤的生物标记物

急性呼吸窘迫综合征(ARDS)和急性肺损伤(ALI)多由低氧性呼吸衰竭引起,导致高通透性肺水肿,临床上有较高的发病率与死亡率。近十年来,针对血浆和支气管肺泡灌洗液中相关生物标记物的研究为探索急性肺损伤的病理生理机制指明了新的方向。个别生物标记物已在一些大型、多中心ARDS试验中得到证实。但迄今仍没有一个或一组生物标记物常规应用于临床。随着人类对ALI发病机制理解的进一步深入,或许不久的将来,生物标记物会真正应用于评估疾病的严重程度和预后。本文将概述近年来ALI相关生物标记物的研究进展。     

Caveolin-1: a critical regulator of lung injury

Caveolin-1 (cav-1), a 22-kDa transmembrane scaffolding protein, is the principal structural component of caveolae. Cav-1 regulates critical cell functions including proliferation, apoptosis, cell differentiation, and transcytosis via diverse signaling pathways. Abundant in almost every cell type in the lung, including type I epithelial cells, endothelial cells, smooth muscle cells, fibroblasts, macrophages, and neutrophils, cav-1 plays a crucial role in the pathogenesis of acute lung injury (ALI). ALI and its severe form, acute respiratory distress syndrome (ARDS), are responsible for significant morbidity and mortality in intensive care units, despite improvement in ventilation strategies. The pathogenesis of ARDS is still poorly understood, and therapeutic options remain limited. In this article, we summarize recent data regarding the regulation and function of cav-1 in lung biology and pathology, in particular as it relates to ALI. We further discuss the potential molecular and cellular mechanisms by which cav-1 expression contributes to ALI. Investigating the cellular functions of cav-1 may provide new insights for understanding the pathogenesis of ALI and provide novel targets for therapeutic interventions in the future.     

Association of IL-10?1082 G/G genotype with lower mortality of acute respiratory distress syndrome in a Chinese population

We aimed to investigate whether interleukin-10 (IL-10) -1082 G/G genotype is associated with lower mortality of acute respiratory distress syndrome (ARDS) in a Chinese population. A hospital-based case-control study was conducted in 314 cases of ARDS and 210 controls who were admitted to an intensive care unit with sepsis, trauma, aspiration or massive transfusions. Cases were followed for 30-day mortality. The -1082G/G genotype was associated with lower development of ARDS (OR=0.51; 95% CI 0.34-0.76; P=0.001). Among patients with ARDS, the -1082G/G genotype was associated with lower 30-day mortality (OR=0.44; 95% CI 0.25-0.76; P=0.003). In conclusion, IL-10-1082 G/G genotype is associated with lower development and mortality of ARDS in a Chinese population.     

肺泡表面活性物质（PS）对盐酸吸入性肺损伤的治疗进展

急性肺损伤／急性呼吸窘迫综合征（ALI/ARDS）是临床上常见的危重症,治疗措施包括机械通气及药物综合治疗。肺泡表面活性物质（PS）在维持正常的肺功能起着重要作用,业已证明,PS异常与ALI／ARDS的发病有关,给予外源性PS亦可治疗ALI／ARDS。本文就外源性PS在盐酸吸入性ALI／ARDS的第二时相中的疗效及其可能的作用机制做一综述。     

The molecular basis of familial hypercholesterolemia in The Netherlands

Mutations in the low-density lipoprotein (LDL) receptor gene are responsible for familial hypercholesterolemia (FH). At present, more than 600 mutations in this gene are known to underlie FH. However, the array of mutations varies considerably in different populations. Therefore, the delineation of essentially all LDL-receptor gene mutations in a population is a prerequisite for the implementation of nation-wide genetic testing for FH. In the Netherlands, mutation analysis by denaturing gradient gel electrophoresis and sequencing in 1641 clinically diagnosed FH patients resulted in the characterization of 159 different LDL-receptor gene defects. The nine most common mutations were responsible for 66.5% of our FH index cases. Of these, four mutations occurred with relatively high frequencies in specific parts of the Netherlands. The remaining mutations were only encountered in single FH patients, comprising 22.2% of the patient cohort analyzed. Subsequent genetic testing of relatives of the index cases within the national FH screening program resulted in the identification of 5,531 FH patients in total. The analysis for LDL-receptor mutations is a continuing effort to update the LDL-receptor mutation catalogue. Subsequently, with the newly generated index cases, the screening program can be extended and continued to identify and treat FH patients as early as possible and reduce cardiovascular morbidity and mortality in these patients at high risk.     

ALI/ARDS患者使用保护性通气策略对于肺部损伤的影响

急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)是常见的临床综合征,绝大多数ALI/ARDS患者需机械通气治疗,机械通气在提供可接受的肺部气体交换的同时治疗基础疾病,但机械通气本身也会引起肺部损伤,即机械通气性肺损伤(VILI)。而通过调整机械通气参数的设置,使用保护性通气策略可显著减低ALI/ARDS患者机械通气性肺损伤程度,从而减少肺部感染,缩短机械通气时间和住院时间,降低28天死亡率,明显改善ALI/ARDS患者的生存质量,起到最大程度地肺保护作用。本文从气道平台压,通气容积,呼气末正压等几个不同通气参数方面分别进行综述,讨论ALI/ARDS患者机械通气时使用保护性通气策略对于肺部损伤的影响。     

Metabolic profiling in human lung injuries by high-resolution nuclear magnetic resonance spectroscopy of bronchoalveolar lavage fluid (BALF)

We present a method for identifying biomarkers in human lung injury. The method is based on high-resolution nuclear magnetic resonance (NMR) spectroscopy applied to bronchoalveolar lavage fluid (BALF) collected from lungs of critically ill patients. This biological fluid can be obtained by bronchoscopic and non-bronchoscopic methods. The type of lung injury in acute respiratory failure presenting as acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), continues to challenge critical care physicians. We characterize different metabolites in BAL fluid by non-bronchoscopic method (mBALF) for better diagnosis and understanding of ALI/ARDS by NMR spectroscopy. NMR spectra of mBALF collected from 30 patients (9 controls, 10 ARDS and 11 ALI) were analyzed for the identification of biomarkers. Statistical methods such as principal components analysis and partial least square discriminant analysis were carried out on ¹H NMR spectrum of mBALF to identify biomarker responsible for separation among different lung injuries classes (ALI and ARDS) and normal lungs. The corresponding correlation of biomarkers with metabolic cycle has given insight into metabolism of lung injuries in critically ill patients. Our study shows statistically significant differentiation of various metabolites concentration in mBALF collected from lungs of ALI, ARDS and healthy control patients, making NMR spectroscopy as a possible new method of characterizing human lung injury.     

Identification of Novel Single Nucleotide Polymorphisms Associated with Acute Respiratory Distress Syndrome by Exome-Seq

Acute respiratory distress syndrome (ARDS) is a lung condition characterized by impaired gas exchange with systemic release of inflammatory mediators, causing pulmonary inflammation, vascular leak and hypoxemia. Existing biomarkers have limited effectiveness as diagnostic and therapeutic targets. To identify disease-associating variants in ARDS patients, whole-exome sequencing was performed on 96 ARDS patients, detecting 1,382,399 SNPs. By comparing these exome data to those of the 1000 Genomes Project, we identified a number of single nucleotide polymorphisms (SNP) which are potentially associated with ARDS. 50,190SNPs were found in all case subgroups and controls, of which89 SNPs were associated with susceptibility. We validated three SNPs (rs78142040, rs9605146 and rs3848719) in additional ARDS patients to substantiate their associations with susceptibility, severity and outcome of ARDS. rs78142040 (C>T) occurs within a histone mark (intron 6) of the Arylsulfatase D gene. rs9605146 (G>A) causes a deleterious coding change (proline to leucine) in the XK, Kell blood group complex subunit-related family, member 3 gene. rs3848719 (G>A) is a synonymous SNP in the Zinc-Finger/Leucine-Zipper Co-Transducer NIF1 gene. rs78142040, rs9605146, and rs3848719 are associated significantly with susceptibility to ARDS. rs3848719 is associated with APACHE II score quartile. rs78142040 is associated with 60-day mortality in the overall ARDS patient population. Exome-seq is a powerful tool to identify potential new biomarkers for ARDS. We selectively validated three SNPs which have not been previously associated with ARDS and represent potential new genetic biomarkers for ARDS. Additional validation in larger patient populations and further exploration of underlying molecular mechanisms are warranted.     

Promising genes and variants to reduce chemotherapy adverse effects in acute lymphoblastic leukemia

Almost two decades ago, the sequencing of the human genome and high throughput technologies came to revolutionize the clinical and therapeutic approaches of patients with complex human diseases. In acute lymphoblastic leukemia (ALL), the most frequent childhood malignancy, these technologies have enabled to characterize the genomic landscape of the disease and have significantly improved the survival rates of ALL patients. Despite this, adverse reactions from treatment such as toxicity, drug resistance and secondary tumors formation are still serious consequences of chemotherapy, and the main obstacles to reduce ALL-related mortality. It is well known that germline variants and somatic mutations in genes involved in drug metabolism impact the efficacy of drugs used in oncohematological diseases therapy. So far, a broader spectrum of clinically actionable alterations that seems to be crucial for the progression and treatment response have been identified. Although these results are promising, it is necessary to put this knowledge into the clinics to help physician make medical decisions and generate an impact in patients’ health. This review summarizes the gene variants and clinically actionable mutations that modify the efficacy of antileukemic drugs. Therefore, knowing their genetic status before treatment is critical to reduce severe adverse effects, toxicities and life-threatening consequences in ALL patients.     

Epidemiology, species distribution, antifungal susceptibility and outcome of nosocomial candidemia in a tertiary care hospital in Italy

Candida is an important cause of bloodstream infections (BSI), causing significant mortality and morbidity in health care settings. From January 2008 to December 2010 all consecutive patients who developed candidemia at San Martino University Hospital, Italy were enrolled in the study. A total of 348 episodes of candidaemia were identified during the study period (January 2008-December 2010), with an incidence of 1,73 episodes/1000 admissions. Globally, albicans and non-albicans species caused around 50% of the cases each. Non-albicans included Candida parapsilosis (28.4%), Candida glabrata (9.5%), Candida tropicalis (6.6%), and Candida krusei (2.6%). Out of 324 evaluable patients, 141 (43.5%) died within 30 days from the onset of candidemia. C. parapsilosis candidemia was associated with the lowest mortality rate (36.2%). In contrast, patients with C. krusei BSI had the highest mortality rate (55.5%) in this cohort. Regarding the crude mortality in the different units, patients in Internal Medicine wards had the highest mortality rate (54.1%), followed by patients in ICU and Hemato-Oncology wards (47.6%).This report shows that candidemia is a significant source of morbidity in Italy, with a substantial burden of disease, mortality, and likely high associated costs. Although our high rates of candidemia may be related to high rates of BSI in general in Italian public hospitals, reasons for these high rates are not clear and warrant further study. Determining factors associated with these high rates may lead to identifying measures that can help to prevent disease.     

乌司他丁对急性肺损伤/急性呼吸窘迫综合征的治疗研究

目的研究大剂量乌司他丁在急性肺损伤/急性呼吸窘迫综合征中的治疗效果。方法回顾性分析2006年1月至2010年1月广西医科大学第一附属医院ICU收治的154例ALI/ARDS患者的临床资料,根据治疗方案分为乌司他丁组(UTI组)(n=80),对照组(n=74)。记录两组患者开始治疗、治疗第3天、治疗第7天的生命体征、动脉血气分析、血生化检查结果;记录患者在ICU治疗的转归。应用SPSS 13.0软件对结果进行统计学分析。结果经治疗3天UTI组呼吸频率低于对照组;动脉血气分析提示两组患者PaO2、PaO2/Fi O2、SaO2均有上升,UTI组PaO2/Fi O2略低于对照组(P0.01),而两组患者PaO2、SaO2比较无统计学差异。UTI组与对照组的死亡率比较(UTI组52.5%,对照组52.7%,P=0.980)无统计学差异,机械通气时间UTI组低于对照组[UTI组(14.8±3.9)天,对照组(16.7±4.2)天,P=0.020]。根据ALI/ARDS发生的病因分为肺内源性及肺外源性进行亚组分析(A组:肺内源性ALI/ARDS,使用UTI治疗;B组:肺内源性ALI/ARDS,不使用UTI治疗;C组:肺外源性ALI/ARDS,使用UTI治疗;D组:肺外源性ALI/ARDS,不使用UTI治疗),发现乌司他丁对肺外源性ALI/ARDS患者(C组)的ICU时间、ICU内死亡率及机械通气时间均低于不使用UTI的患者(D组)。结论大剂量乌司他丁用于ALI/ARDS的临床治疗可有效改善患者氧合指数,减少机械通气时间,且高血糖的发生率低,尤其是乌司他丁治疗肺外源性ALI/ARDS患者的预后优于肺内源性的ALI/ARDS。     

Integration of human and mouse genetics reveals pendrin function in hearing and deafness

Genomic technology has completely changed the way in which we are able to diagnose human genetic mutations. Genomic techniques such as the polymerase chain reaction, linkage analysis, Sanger sequencing, and most recently, massively parallel sequencing, have allowed researchers and clinicians to identify mutations for patients with Pendred syndrome and DFNB4 non-syndromic hearing loss. While thus far most of the mutations have been in the SLC26A4 gene coding for the pendrin protein, other genetic mutations may contribute to these phenotypes as well. Furthermore, mouse models for deafness have been invaluable to help determine the mechanisms for SLC26A4-associated deafness. Further work in these areas of research will help define genotype-phenotype correlations and develop methods for therapy in the future.     

A single centered study reveals association between liver injury and COVID-19 infection

Background and aimDespite the fact that it has been over a year with the pandemic COVID-19 infection, ongoing research and analysis reveal many complications and comorbidities associated with COVID-19. In this study, we aimed at investigating the clinical and laboratory assessments in COVID-19 patients with and without liver injury.MethodsSymptomatic 541 COVID-19 positive patients, who were admitted to Al Kuwait Hospital, Dubai, United Arab Emirates (UAE), were recruited in this study. Their data was collected retrospectively, including demographic data, blood tests, symptoms, radiographical assessments, and clinical outcomes of COVID-19.ResultsAround 19% of the recruited COVID-19 patients displayed signs of acute liver injury. Also, there was an increase in the percentage of critical, ICU-admitted and mortality rates in COVID-19 cases with liver injury, as well as a higher percentage of septic shock and acute respiratory distress syndrome (ARDS). COVID-19 patients with liver injury had more pronounced bilateral consolidation, lymphopenia and neutrophilia. Additionally, these patients had higher levels of CRP, LDH, procalcitonin, ferritin and D dimer levels. Finally, there was a higher percentage of patients taking various COVID-19 therapies in the COVID-19 patients with liver injury group.ConclusionCOVID-19 patients with acute liver injury are at a higher risk for serious outcomes including death.