Publications (27) View all
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Article: Chest Computed Tomography Features Are Associated With Poorer Quality of Life in Acute Lung Injury Survivors.
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ABSTRACT: OBJECTIVES:: Despite decreasing mortality rates in acute lung injury, studies of long-term physical function in acute lung injury survivors have consistently reported poorer quality of life persisting years into recovery for reasons that are not completely understood. We sought to determine if pulmonary dysfunction is independently associated with functional impairment among acute lung injury survivors and to determine if high-resolution computed tomography could be used to predict its development. DESIGN:: Secondary analysis of data from a randomized controlled trial in acute lung injury. SETTING:: ICUs at three academic medical centers. PATIENTS:: Patients diagnosed with acute lung injury who had high-resolution computed tomography scans performed at 14 and/or 180 days after diagnosis. INTERVENTIONS:: None. MEASUREMENTS AND MAIN RESULTS:: An objective radiologic scoring system was used to quantify patterns present on chest high-resolution computed tomography obtained at 14 and 180 days in patients with acute lung injury. These scores were correlated in univariable and multivariable analyses with pulmonary function testing and quality of life survey data obtained at 180 days. Eighty-nine patients had evaluable data at day 14, and 47 at 180 days. At 180 days, increased radiologic scores for reticulation were associated with a decreased total lung capacity, forced vital capacity, and diffusing capacity for carbon monoxide (p values all < 0.002). Decrements in quality of life attributable to pulmonary dysfunction were most strongly associated with higher radiologic scores. Additionally, radiologic scores at 14 days independently predicted poorer quality of life at 180 days, accounting for age, severity of illness, pneumonia as the acute lung injury risk factor, and length of time on mechanical ventilation. CONCLUSIONS:: Among survivors of acute lung injury, increasing chest high-resolution computed tomography involvement correlated with restrictive physiology and poorer health-related quality of life, implicating pulmonary dysfunction as a potential contributor to activity limitation in these patients.Critical care medicine 12/2012; · 6.37 Impact Factor -
Article: Effect of alveolar epithelial cell plasticity on the regulation of GM-CSF expression.
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ABSTRACT: Local pulmonary expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) is critically important for defense of the pulmonary alveolar space. It is required for surfactant homeostasis and pulmonary innate immune responses and is protective against lung injury and aberrant repair. Alveolar epithelial cells (AEC) are a major source of GM-CSF; however, the control of homeostatic expression of GM-CSF is incompletely characterized. Increasing evidence suggests considerable plasticity of expression of AEC phenotypic characteristics. We tested the hypothesis that this plasticity extends to regulation of expression of GM-CSF using 1) MLE-12 cells (a commonly used murine cell line expressing some features of normal type II AEC, 2) primary murine AEC incubated under standard conditions [resulting in rapid spreading and loss of surfactant protein C (SP-C) expression with induction of the putative type I cell marker (T1α)], or 3) primary murine AEC on a hyaluronic acid/collagen matrix in defined medium, resulting in preservation of SP-C expression. AEC in standard cultures constitutively express abundant GM-CSF, with further induction in response to IL-1β but little response to TNF-α. In contrast, primary cells cultured to preserve SP-C expression and MLE-12 cells both express little GM-CSF constitutively, with significant induction in response to TNF-α and limited response to IL-1β. We conclude that constitutive and cytokine-induced expression of GM-CSF by AEC varies in concert with other cellular phenotypic characteristics. These changes may have important implications both for the maintenance of normal pulmonary homeostasis and for the process of repair following lung injury.AJP Lung Cellular and Molecular Physiology 01/2012; 302(6):L504-11. · 3.66 Impact Factor -
Article: GM-CSF provides autocrine protection for murine alveolar epithelial cells from oxidant-induced mitochondrial injury.
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ABSTRACT: Exposure of mice to hyperoxia induces alveolar epithelial cell (AEC) injury, acute lung injury and death. Overexpression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the lung protects against these effects, although the mechanisms are not yet clear. Hyperoxia induces cellular injury via effects on mitochondrial integrity, associated with induction of proapoptotic members of the Bcl-2 family. We hypothesized that GM-CSF protects AEC through effects on mitochondrial integrity. MLE-12 cells (a murine type II cell line) and primary murine type II AEC were subjected to oxidative stress by exposure to 80% oxygen and by exposure to H(2)O(2). Exposure to H(2)O(2) induced cytochrome c release and decreased mitochondrial reductase activity in MLE-12 cells. Incubation with GM-CSF significantly attenuated these effects. Protection induced by GM-CSF was associated with Akt activation. GM-CSF treatment also resulted in increased expression of the antiapoptotic Bcl-2 family member, Mcl-1. Primary murine AEC were significantly more tolerant of oxidative stress than MLE-12 cells. In contrast to MLE-12 cells, primary AEC expressed significant GM-CSF at baseline and demonstrated constitutive activation of Akt and increased baseline expression of Mcl-1. Treatment with exogenous GM-CSF further increased Akt activation and Mcl-1 expression in primary AEC. Conversely, suppression of AEC GM-CSF expression by use of GM-CSF-specific small interfering RNA resulted in decreased tolerance of oxidative stress, Furthermore, silencing of Mcl-1 prevented GM-CSF-induced protection. We conclude that GM-CSF protects alveolar epithelial cells against oxidative stress-induced mitochondrial injury via the Akt pathway and its downstream components, including Mcl-1. Epithelial cell-derived GM-CSF may contribute to intrinsic defense mechanisms limiting lung injury.AJP Lung Cellular and Molecular Physiology 12/2011; 302(3):L343-51. · 3.66 Impact Factor -
Article: A randomized trial of recombinant human granulocyte-macrophage colony stimulating factor for patients with acute lung injury.
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ABSTRACT: Despite recent advances in critical care and ventilator management, acute lung injury and acute respiratory distress syndrome continue to cause significant morbidity and mortality. Granulocyte-macrophage colony stimulating factor may be beneficial for patients with acute respiratory distress syndrome. To determine whether intravenous infusion of granulocyte-macrophage colony stimulating factor would improve clinical outcomes for patients with acute lung injury/acute respiratory distress syndrome. A randomized, double-blind, placebo-controlled clinical trial of human recombinant granulocyte-macrophage colony stimulating factor vs. placebo. The primary outcome was days alive and breathing without mechanical ventilatory support within the first 28 days after randomization. Secondary outcomes included mortality and organ failure-free days. Medical and surgical intensive care units at three academic medical centers. One hundred thirty individuals with acute lung injury of at least 3 days duration were enrolled, out of a planned cohort of 200 subjects. Patients were randomized to receive human recombinant granulocyte-macrophage colony stimulating factor (64 subjects, 250 μg/M) or placebo (66 subjects) by intravenous infusion daily for 14 days. Patients received mechanical ventilation using a lung-protective protocol. There was no difference in ventilator-free days between groups (10.7 ± 10.3 days placebo vs. 10.8 ± 10.5 days granulocyte-macrophage colony stimulating factor, p = .82). Differences in 28-day mortality (23% in placebo vs. 17% in patients receiving granulocyte-macrophage colony stimulating factor (p = .31) and organ failure-free days (12.8 ± 11.3 days placebo vs. 15.7 ± 11.9 days granulocyte-macrophage colony stimulating factor, p = .16) were not statistically significant. There were similar numbers of serious adverse events in each group. In a randomized phase II trial, granulocyte-macrophage colony stimulating factor treatment did not increase the number of ventilator-free days in patients with acute lung injury/acute respiratory distress syndrome. A larger trial would be required to determine whether treatment with granulocyte-macrophage colony stimulating factor might alter important clinical outcomes, such as mortality or multiorgan failure. (ClinicalTrials.gov number, NCT00201409 [ClinicalTrials.gov]).Critical care medicine 09/2011; 40(1):90-7. · 6.37 Impact Factor -
Article: Overexpression of sICAM-1 in the Alveolar Epithelial Space Results in an Exaggerated Inflammatory Response and Early Death in Gram Negative Pneumonia
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ABSTRACT: Abstract Background A sizeable body of data demonstrates that membrane ICAM-1 (mICAM-1) plays a significant role in host defense in a site-specific fashion. On the pulmonary vascular endothelium, mICAM-1 is necessary for normal leukocyte recruitment during acute inflammation. On alveolar epithelial cells (AECs), we have shown previously that the presence of normal mICAM-1 is essential for optimal alveolar macrophage (AM) function. We have also shown that ICAM-1 is present in the alveolar space as a soluble protein that is likely produced through cleavage of mICAM-1. Soluble intercellular adhesion molecule-1 (sICAM-1) is abundantly present in the alveolar lining fluid of the normal lung and could be generated by proteolytic cleavage of mICAM-1, which is highly expressed on type I AECs. Although a growing body of data suggesting that intravascular sICAM-1 has functional effects, little is known about sICAM-1 in the alveolus. We hypothesized that sICAM-1 in the alveolar space modulates the innate immune response and alters the response to pulmonary infection. Methods Using the surfactant protein C (SPC) promoter, we developed a transgenic mouse (SPC-sICAM-1) that constitutively overexpresses sICAM-1 in the distal lung, and compared the responses of wild-type and SPC-sICAM-1 mice following intranasal inoculation with K. pneumoniae. Results SPC-sICAM-1 mice demonstrated increased mortality and increased systemic dissemination of organisms compared with wild-type mice. We also found that inflammatory responses were significantly increased in SPC-sICAM-1 mice compared with wild-type mice but there were no difference in lung CFU between groups. Conclusions We conclude that alveolar sICAM-1 modulates pulmonary inflammation. Manipulating ICAM-1 interactions therapeutically may modulate the host response to Gram negative pulmonary infections.Respiratory Research. 01/2011;
