Kinetics and Role of Plasma Matrix Metalloproteinase-9 Expression in Acute Lung Injury and the Acute Respiratory Distress Syndrome.

Primed neutrophils that are capable of releasing matrix metalloproteinases (MMPs) into the circulation are thought to play a significant role in the pathophysiology of acute respiratory distress syndrome (ARDS). We hypothesized that direct measurement of plasma MMP-9 activity may be a predictor of incipient tissue damage and subsequent lung injury, which was investigated in both an animal model of ARDS and a small cohort of 38 critically ill human patients. In a mouse model of ARDS involving instillation of intratracheal lipopolysaccharide (LPS) to induce lung inflammation, we measured neutrophil-mediated inflammation, along with MMP-9 activity in the airways and lung tissue and MMP-9 expression in the plasma. Neutrophil recruitment, inflammation, and MMP-9 activity in the airways and lung tissue increased throughout the 72 h after LPS instillation, whereas plasma MMP-9 expression was greatest at 12 to 24 h after LPS instillation. The results suggest that the peak in plasma MMP-9 activity may precede the peak of neutrophil inflammation in the airways and lung tissue in the setting of ARDS. Based on this animal study, a retrospective observational cohort study involving 38 patients admitted to a surgical intensive care unit at a tertiary care university hospital with acute respiratory failure requiring intubation and mechanical ventilation was conducted. Plasma samples were collected daily, and MMP-9 activity was compared with lung function as determined by the PaO2/FiO2 ratio. In patients who developed ARDS, a notable increase in plasma MMP-9 activity on a particular day correlated with a decrease in the PaO2/FiO2 ratio on the following day (r = -0.503, P < 0.006). Taken together, these results suggest that plasma MMP-9 activity changes, as a surrogate for primed neutrophils may have predictive value for the development of ARDS in a selected subset of critically ill patients.

Clinical characteristics and outcomes of sepsis-related vs non-sepsis-related ARDS.

BACKGROUND: ARDS may occur after either septic or nonseptic injuries. Sepsis is the major cause of ARDS, but little is known about the differences between sepsis-related and non-sepsis-related ARDS. METHODS: A total of 2,786 patients with ARDS-predisposing conditions were enrolled consecutively into a prospective cohort, of which 736 patients developed ARDS. We defined sepsis-related ARDS as ARDS developing in patients with sepsis and non-sepsis-related ARDS as ARDS developing after nonseptic injuries, such as trauma, aspiration, and multiple transfusions. Patients with both septic and nonseptic risks were excluded from analysis. RESULTS: Compared with patients with non-sepsis-related ARDS (n = 62), patients with sepsis-related ARDS (n = 524) were more likely to be women and to have diabetes, less likely to have preceding surgery, and had longer pre-ICU hospital stays and higher APACHE III (Acute Physiology and Chronic Health Evaluation III) scores (median, 78 vs 65, P < .0001). There were no differences in lung injury score, blood pH, Pao(2)/Fio(2) ratio, and Paco(2) on ARDS diagnosis. However, patients with sepsis-related ARDS had significantly lower Pao(2)/Fio(2) ratios than patients with non-sepsis-related ARDS patients on ARDS day 3 (P = .018), day 7 (P = .004), and day 14 (P = .004) (repeated-measures analysis, P = .011). Compared with patients with non-sepsis-related ARDS, those with sepsis-related had a higher 60-day mortality (38.2% vs 22.6%; P = .016), a lower successful extubation rate (53.6% vs 72.6%; P = .005), and fewer ICU-free days (P = .0001) and ventilator-free days (P = .003). In multivariate analysis, age, APACHE III score, liver cirrhosis, metastatic cancer, admission serum bilirubin and glucose levels, and treatment with activated protein C were independently associated with 60-day ARDS mortality. After adjustment, sepsis-related ARDS was no longer associated with higher 60-day mortality (hazard ratio, 1.26; 95% CI, 0.71-2.22). CONCLUSION: Sepsis-related ARDS has a higher overall disease severity, poorer recovery from lung injury, lower successful extubation rate, and higher mortality than non-sepsis-related ARDS. Worse clinical outcomes in sepsis-related ARDS appear to be driven by disease severity and comorbidities.

Genetic variants in the angiopoietin-2 gene are associated with increased risk of ARDS.

OBJECTIVE: Angiopoietin-2 (Ang-2) is a potent regulator of vascular permeability and inflammation in acute lung injury and acute respiratory distress syndrome (ARDS). Genetic variants in the Ang-2 gene may lead to altered activities of Ang-2 (or ANGPT2) gene. The aim of this study was to assess if genetic variants of Ang-2 are associated with the risk of ARDS. DESIGN: Unmatched, case-control study nested within a prospectively enrolled cohort. SETTING: Intensive care units (ICU) of an academic medical center. PATIENTS: About 1,529 critically ill patients with risk factors for ARDS consecutively admitted to the ICUs from 1999 to 2006. Cases were 449 patients who developed ARDS and controls were 1,080 subjects who did not developed ARDS. INTERVENTION: None. MEASUREMENTS AND RESULTS: Nine tagging SNPs (tSNPs) spanning the entire Ang-2 gene were genotyped in all patients. The results were analyzed using logistic regression models, adjusting for covariates. The variant T allele of one tSNP (rs2515475) was significantly associated with increased risk of ARDS (OR(adjusted) = 1.28; P = 0.042). This association was stronger in subjects with extrapulmonary injuries (OR(adjusted) = 1.79; P = 0.004). Haplotype TT in block 2 containing the T allele of the rs2515475 was also significantly associated with higher risk of ARDS (OR(adjusted) = 1.42; P = 0.009), particularly in subjects with extrapulmonary injuries (OR(adjusted) = 1.90; P = 0.004). CONCLUSION: Common genetic variation in the Ang-2 gene may be associated with increased risk of ARDS, especially among patients with extrapulmonary injuries.

Circulating angiopoietin 2 correlates with mortality in a surgical population with acute lung injury/adult respiratory distress syndrome.

There are few blood biomarkers predictive of mortality in adult respiratory distress syndrome (ARDS), and none that currently serve as therapeutic targets. Here, we ask whether a circulating protein angiopoietin 2 (Ang2) correlates with severity of lung injury and mortality in a surgical intensive care unit cohort with acute lung injury (ALI)/ARDS. Tie 2 is a tyrosine kinase receptor expressed on endothelial cells. One ligand, angiopoietin 1, phosphorylates Tie 2 and stabilizes adult vasculature. An alternate ligand, Ang2, serves as a context-dependent antagonist and disrupts barrier function. Previously, our laboratory detected high circulating Ang2 levels in septic patients and a correlation with low Pa(O2)/F(IO2). In this study, daily plasma was collected in 63 surgical intensive care unit patients. Eighteen patients met clinical criteria for ALI or ARDS. The median Ang2 at admission in patients who never developed ALI/ARDS was 3.7 ng/mL (interquartile range [IQR], 5.6; n = 45). The Ang2 on the day a patient met criteria for ALI/ARDS was 5.3 ng/mL (IQR, 6.7) for survivors (n = 11) and 19.8 ng/mL (IQR, 19.2) for nonsurvivors (n = 7; P= 0.004). To explore the mechanism of high Ang 2 leading to increased permeability, plasma from patients with ALI was applied to cultured lung endothelial cells and found to disrupt normal junctional architecture. This effect can be rescued with the Tie 2 agonist angiopoietin 1. A patient's convalescent (low Ang2) plasma did not disrupt junctional architecture. Although further studies with larger sample sizes will be needed to confirm these results, high Ang2 in critically ill patients with ALI/ARDS is associated with a poor outcome. These data, coupled with our cell culture experiments, suggest that antagonism of Ang2 may provide a future novel therapeutic target for ARDS.

Angiopoietin 2 is a potential mediator of high-dose interleukin 2-induced vascular leak.

PURPOSE: High-dose interleukin 2 (HDIL2) produces durable tumor regressions in 10% of patients with metastatic renal cell carcinoma and melanoma. However, a major toxicity is vascular leak syndrome (VLS). We previously reported elevated serum angiopoietin 2 (Ang2) in septic patients with vascular leak and hypothesized that Ang2 might also contribute to HDIL2 VLS. EXPERIMENTAL DESIGN: Blood was collected from 14 patients receiving HDIL2 and from 4 patients receiving HDIL2 and bevacizumab, an antibody against vascular endothelial growth factor (VEGF). The effect of Ang2 was studied in vitro by incubating high Ang2 patient serum with cultured endothelial cells. RESULTS: Pretreatment Ang2 levels were in the reference range (median, 3.3 ng/mL) and rose with each day of IL-2 therapy (median peak, 29.7 ng/mL). No trend was seen in free VEGF levels during therapy. Patients treated with HDIL2 and bevacizumab all developed VLS and elevated Ang2. High Ang2 patient sera induced propermeability structural changes in endothelial cells, an effect reversed by blockade with the competitive ligand angiopoietin 1 (Ang1). CONCLUSIONS: Ang2 may be a mediator of HDIL2 VLS as evidenced by (a) an increase in Ang2 in all patients on HDIL2; (b) the effect of high Ang2 patient serum on cultured endothelial cells; (c) rescue of those structural changes by Ang1. The lack of correlation between VLS and serum VEGF levels in patients treated with HDIL2 alone or in combination with bevacizumab suggests that VEGF is not a major contributor to VLS or Ang2 release. These data suggest that the inhibition of Ang2 may mitigate VLS in patients receiving HDIL2.

Expiratory abdominal rounding in acute dyspnea suggests congestive heart failure.

Patients in acute respiratory distress require rapid assessment of the cause of dyspnea. We have observed that many of those patients who are in congestive heart failure (CHF) exhibit rounding of the abdominal cross-section during expiration. We sought to evaluate the diagnostic utility of this breathing pattern in dyspneic patients presenting to an emergency department. Twenty-six subjects with dyspnea due to a variety of conditions were recruited from the emergency department at Beth Israel Deaconess Medical Center. Subjects ranged in age from 21 to 94 years and 81% were female. We measured variation in the anteroposterior and transverse diameters of the rib cage and abdomen using respiratory magnetometers and determined phase of respiration with a pneumotachometer. Investigators blinded to the subjects' identities and diagnoses interpreted measurements as indicating normal respiratory movement without expiratory abdominal rounding, slight expiratory rounding, or pronounced expiratory rounding. The likely cause of dyspnea was determined from discharge diagnoses in the medical record. Expiratory rounding was observed in 12/14 subjects with CHF and 5/12 subjects without CHF (p = 0.0186), and pronounced expiratory rounding was present in 11/14 patients with CHF and 2/12 patients without CHF (p = 0.0016). Test characteristics for the association of CHF with pronounced expiratory rounding were sensitivity 79%, specificity 83%, and predictive accuracy 81%. In patients with acute respiratory distress, expiratory abdominal rounding suggests CHF as the primary cause of dyspnea; a greater degree of rounding suggests a greater likelihood of CHF. The clinical utility of this diagnostic sign remains to be determined in a prospective study.