Project description:Background and objectiveNeonatal respiratory distress syndrome (RDS) due to pulmonary surfactant deficiency is heritable, but common variants do not fully explain disease heritability.MethodsUsing next-generation, pooled sequencing of race-stratified DNA samples from infants ?34 weeks' gestation with and without RDS (n = 513) and from a Missouri population-based cohort (n = 1066), we scanned all exons of 5 surfactant-associated genes and used in silico algorithms to identify functional mutations. We validated each mutation with an independent genotyping platform and compared race-stratified, collapsed frequencies of rare mutations by gene to investigate disease associations and estimate attributable risk.ResultsSingle ABCA3 mutations were overrepresented among European-descent RDS infants (14.3% of RDS vs 3.7% of non-RDS; P = .002) but were not statistically overrepresented among African-descent RDS infants (4.5% of RDS vs 1.5% of non-RDS; P = .23). In the Missouri population-based cohort, 3.6% of European-descent and 1.5% of African-descent infants carried a single ABCA3 mutation. We found no mutations among the RDS infants and no evidence of contribution to population-based disease burden for SFTPC, CHPT1, LPCAT1, or PCYT1B.ConclusionsIn contrast to lethal neonatal RDS resulting from homozygous or compound heterozygous ABCA3 mutations, single ABCA3 mutations are overrepresented among European-descent infants ?34 weeks' gestation with RDS and account for ~10.9% of the attributable risk among term and late preterm infants. Although ABCA3 mutations are individually rare, they are collectively common among European- and African-descent individuals in the general population.
Project description:The acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in critically ill patients and is defined by the acute onset of noncardiogenic pulmonary oedema, hypoxaemia and the need for mechanical ventilation. ARDS occurs most often in the setting of pneumonia, sepsis, aspiration of gastric contents or severe trauma and is present in ~10% of all patients in intensive care units worldwide. Despite some improvements, mortality remains high at 30-40% in most studies. Pathological specimens from patients with ARDS frequently reveal diffuse alveolar damage, and laboratory studies have demonstrated both alveolar epithelial and lung endothelial injury, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Diagnosis is based on consensus syndromic criteria, with modifications for under-resourced settings and in paediatric patients. Treatment focuses on lung-protective ventilation; no specific pharmacotherapies have been identified. Long-term outcomes of patients with ARDS are increasingly recognized as important research targets, as many patients survive ARDS only to have ongoing functional and/or psychological sequelae. Future directions include efforts to facilitate earlier recognition of ARDS, identifying responsive subsets of patients and ongoing efforts to understand fundamental mechanisms of lung injury to design specific treatments.
Project description:Acute respiratory distress syndrome (ARDS) is an acute respiratory illness characterised by bilateral chest radiographical opacities with severe hypoxaemia due to non-cardiogenic pulmonary oedema. The COVID-19 pandemic has caused an increase in ARDS and highlighted challenges associated with this syndrome, including its unacceptably high mortality and the lack of effective pharmacotherapy. In this Seminar, we summarise current knowledge regarding ARDS epidemiology and risk factors, differential diagnosis, and evidence-based clinical management of both mechanical ventilation and supportive care, and discuss areas of controversy and ongoing research. Although the Seminar focuses on ARDS due to any cause, we also consider commonalities and distinctions of COVID-19-associated ARDS compared with ARDS from other causes.
Project description:Bronchoalveolar Lavage Fluid protein profile was characterized in ARDS subjects. Patients were divided into three groups: 1) Early phase survivors 2) Early phase non-survivors and 3) Late phase survivors. Bronchoalveolar lavage fluid was pooled within each group for sample preparation and mass spectrometry
Project description:Acute Respiratory Distress Syndrome (ARDS) continues to have a high mortality. The objective of this study is to understand the differences in disease biology between survivors and non-survivors by characterizing BALF protein expression profiles in individual ARDS subjects.
Project description:The acute respiratory distress syndrome (ARDS) is an important cause of acute respiratory failure that is often associated with multiple organ failure. Several clinical disorders can precipitate ARDS, including pneumonia, sepsis, aspiration of gastric contents, and major trauma. Physiologically, ARDS is characterized by increased permeability pulmonary edema, severe arterial hypoxemia, and impaired carbon dioxide excretion. Based on both experimental and clinical studies, progress has been made in understanding the mechanisms responsible for the pathogenesis and the resolution of lung injury, including the contribution of environmental and genetic factors. Improved survival has been achieved with the use of lung-protective ventilation. Future progress will depend on developing novel therapeutics that can facilitate and enhance lung repair.
Project description:BackgroundSepsis is a major risk factor for acute respiratory distress syndrome (ARDS). However, there remains a paucity of literature examining risk factors for ARDS in septic patients early in their course. This study examined the role of early fluid administration and identified other risk factors within the first 6 h of hospital presentation associated with developing ARDS in septic patients.MethodsThis was a secondary analysis of septic adult patients presenting to the Emergency Department or being admitted for high-risk elective surgery from the multicenter observational cohort study, US Critical Injury and Illness trial Group-Lung Injury Prevention Study 1 (USCIITG-LIPS 1, NCT00889772). Multivariable logistic regression was performed to identify potential early risk factors for ARDS. Stratified analysis by shock status was performed to examine the association between early fluid administration and ARDS.ResultsOf the 5584 patients in the original study cohort, 2534 (45.4%) met our criteria for sepsis. One hundred and fifty-six (6.2%) of these patients developed ARDS during the hospital stay. In multivariable analyses, Acute Physiology and Chronic Health Evaluation (APACHE) II score (OR 1.10, 95% CI 1.07-1.13), age (OR 0.97, 95% CI 0.96-0.98), total fluid infused in the first 6 h (in liters) (OR 1.15, 95% CI 1.03-1.29), shock (OR 2.57, 95% CI 1.62-4.08), pneumonia as a site of infection (OR 2.31, 95% CI 1.59-3.36), pancreatitis (OR 3.86, 95% CI 1.33-11.24), and acute abdomen (OR 3.77, 95% CI 1.37-10.41) were associated with developing ARDS. In the stratified analysis, total fluid infused in the first 6 h (in liters) (OR 1.05, 95% CI 0.87-1.28) was not associated with the development of ARDS in the shock group, while there was an association in the non-shock group (OR 1.21, 95% CI 1.05-1.38).ConclusionsIn septic patients, the following risk factors identified within the first 6 h of hospital presentation were associated with ARDS: APACHE II score, presence of shock, pulmonary source of infection, pancreatitis, and presence of an acute abdomen. In septic patients without shock, the amount of fluid infused during the first 6 h of hospital presentation was associated with developing ARDS.
Project description:Rat model of ARDS was induced by saline lavage and mechanical ventilation. Total RNA from rat lungs were used for dual color DNA microarray hybridization with 3DNA 50 kit version 2. Two-condition experiment, CON vs. ARDS lung tissues. replicates: 5 control, 7 ARDS. One replicate per array.