Early mobilization of critically ill patients with the acute respiratory distress syndrome (ARDS) has emerged as a therapeutic strategy that improves patient outcomes, such as the duration of ...mechanical ventilation and muscle strength. Despite the apparent efficacy of early mobility programs, their use in clinical practice is limited outside of specialized centers and clinical trials. To evaluate the mechanisms underlying mobility therapy, we exercised acute lung injury (ALI) mice for 2 days after the instillation of lipopolysaccharides into their lungs. We found that a short duration of moderate intensity exercise in ALI mice attenuated muscle ring finger 1 (MuRF1)-mediated atrophy of the limb and respiratory muscles and improved limb muscle force generation. Exercise also limited the influx of neutrophils into the alveolar space through modulation of a coordinated systemic neutrophil chemokine response. Granulocyte colony-stimulating factor (G-CSF) concentrations were systemically reduced by exercise in ALI mice, and in vivo blockade of the G-CSF receptor recapitulated the lung exercise phenotype in ALI mice. Additionally, plasma G-CSF concentrations in humans with acute respiratory failure (ARF) undergoing early mobility therapy showed greater decrements over time compared to control ARF patients. Together, these data provide a mechanism whereby early mobility therapy attenuates muscle wasting and limits ongoing alveolar neutrophilia through modulation of systemic neutrophil chemokines in lung-injured mice and humans.
Foxp3
regulatory T cells (Tregs) play essential roles in immune homeostasis and repair of damaged lung tissue. We hypothesized that patients whose lung injury resolves quickly, as measured by time to ...liberation from mechanical ventilation, have a higher percentage of Tregs amongst CD4
T cells in either airway, bronchoalveolar lavage (BAL) or peripheral blood samples.
We prospectively enrolled patients with ARDS requiring mechanical ventilation and collected serial samples, the first within 72 h of ARDS diagnosis (day 0) and the second 48-96 h later (day 3). We analyzed immune cell populations and cytokines in BAL, tracheal aspirates and peripheral blood, as well as cytokines in plasma, obtained at the time of bronchoscopy. The study cohort was divided into fast resolvers (FR; n = 8) and slow resolvers (SR; n = 5), based on the median number of days until first extubation for all participants (n = 13). The primary measure was the percentage of CD4
T cells that were Tregs.
The BAL of FR contained more Tregs than SR. This finding did not extend to Tregs in tracheal aspirates or blood. BAL Tregs expressed more of the full-length FOXP3 than a splice variant missing exon 2 compared to Tregs in simultaneously obtained peripheral blood.
Tregs are present in the bronchoalveolar space during ARDS. A greater percentage of CD4
cells were Tregs in the BAL of FR than SR. Tregs may play a role in the resolution of ARDS, and enhancing their numbers or functions may be a therapeutic target.
Short-term memory load can impair attentional control, but prior work shows that the extent of the effect ranges from being very general to very specific. One factor for the mixed results may be ...reliance on point estimates of memory load effects on attention. Here we used auditory attention gradients as an analog measure to map-out the impact of short-term memory load over space. Verbal or spatial information was maintained during an auditory spatial attention task and compared to no-load. Stimuli were presented from five virtual locations in the frontal azimuth plane, and subjects focused on the midline. Reaction times progressively increased for lateral stimuli, indicating an attention gradient. Spatial load further slowed responses at lateral locations, particularly in the left hemispace, but had little effect at midline. Verbal memory load had no (Experiment 1), or a minimal (Experiment 2) influence on reaction times. Spatial and verbal load increased switch costs between memory encoding and attention tasks relative to the no load condition. The findings show that short-term memory influences the distribution of auditory attention over space; and that the specific pattern depends on the type of information in short-term memory.
The immunologic responses that occur early in the acute respiratory distress syndrome (ARDS) elicit immune‐mediated damage. The mechanisms underlying the resolution of ARDS, particularly the role of ...signaling molecules in regulating immune cell kinetics, remain important questions. Th1‐mediated responses can contribute to the pathogenesis of acute lung injury (ALI). Interferon‐gamma (IFN‐γ) orchestrates early inflammatory events, enhancing immune‐mediated damage. The current study investigated IFN‐γ during resolution in several experimental models of ALI. The absence of IFN‐γ resulted in altered kinetics of lymphocyte and macrophage responses, suggesting that IFN‐γ present in this microenvironment is influential in ALI resolution. Genetic deficiency of IFN‐γ or administering neutralizing IFN‐γ antibodies accelerated the pace of resolution. Neutralizing IFN‐γ decreased the numbers of interstitial and inflammatory macrophages and increased alveolar macrophage numbers during resolution. Our results underline the complexity of lung injury resolution and provide insight into the effects through which altered IFN‐γ concentrations affect immune cell kinetics and the rate of resolution. These findings suggest that therapies that spatially or temporally control IFN‐γ signaling may promote ALI resolution. Identifying and elucidating the mechanisms critical to ALI resolution will allow the development of therapeutic approaches to minimize collateral tissue damage without adversely altering the response to injury.
Neutralizing IFN‐γ decreased the numbers of interstitial and inflammatory macrophages and increased the alveolar macrophage numbers during resolution. These results underline the complexity of lung injury resolution and provide insight into the effects through which altered IFN‐γ concentrations affect immune cell kinetics and the rate of resolution. These findings suggest that therapies that spatially or temporally control IFN‐γ signaling may promote ALI resolution.
Although early events in the pathogenesis of acute lung injury (ALI) have been defined, little is known about the mechanisms mediating resolution. To search for determinants of resolution, we exposed ...wild type (WT) mice to intratracheal LPS and assessed the response at intervals to day 10, when injury had resolved. Inducible NO synthase (iNOS) was significantly upregulated in the lung at day 4 after LPS. When iNOS-/- mice were exposed to intratracheal LPS, early lung injury was attenuated; however, recovery was markedly impaired compared with WT mice. iNOS-/- mice had increased mortality and sustained increases in markers of lung injury. Adoptive transfer of WT (iNOS+/+) bone marrow-derived monocytes or direct adenoviral gene delivery of iNOS into injured iNOS-/- mice restored resolution of ALI. Irradiated bone marrow chimeras confirmed the protective effects of myeloid-derived iNOS but not of epithelial iNOS. Alveolar macrophages exhibited sustained expression of cosignaling molecule CD86 in iNOS-/- mice compared with WT mice. Ab-mediated blockade of CD86 in iNOS-/- mice improved survival and enhanced resolution of lung inflammation. Our findings show that monocyte-derived iNOS plays a pivotal role in mediating resolution of ALI by modulating lung immune responses, thus facilitating clearance of alveolar inflammation and promoting lung repair.
A temporal motor defect in speech preparation and/or planning may contribute to the development of stuttering. This defect may be linked to a dysfunctional cortical-subcortical network at the level ...of the striatum. To determine whether structural differences exist and whether group differences are associated with stuttering severity or manual laterality, the caudate was measured in 14 children who stutter (CWS) and in a control group of right-handed boys, ages 8–13 years. There was a statistically significant hemisphere by group effect for caudate volume. CWS had reduced right caudate volume and atypical leftward asymmetry compared to controls. Nine of the 13 CWS with atypical caudate asymmetry had atypical manual laterality. These anomalies may represent a vulnerability that perturbs speech planning/preparation and contributes to inefficiencies in action-perception coupling that may be an indicator of stuttering susceptibility. These results suggest that right-handed boys who stutter may have a defect in the feedforward cortico-striato-thalamo-cortical networks.
Repair of the lung epithelium after injury is a critical component for resolution; however, the processes necessary to drive epithelial resolution are not clearly defined. Published data demonstrate ...that Foxp3
regulatory T cells (Tregs) enhance alveolar epithelial proliferation after injury, and Tregs in vitro directly promote type II alveolar epithelial cell (AT2) proliferation, in part by a contact-independent mechanism. Therefore, we sought to determine the contribution of Treg-specific expression of a growth factor that is known to be important in lung repair, keratinocyte growth factor (kgf). The data demonstrate that Tregs express kgf and that Treg-specific expression of kgf regulates alveolar epithelial proliferation during the resolution phase of acute lung injury and in a model of regenerative alveologenesis in vivo. In vitro experiments demonstrate that AT2 cells cocultured with Tregs lacking kgf have decreased rates of proliferation compared with AT2 cells cocultured with wild-type Tregs. Moreover, Tregs isolated from lung tissue and grown in culture express higher levels of two growth factors that are important for lung repair (kgf and amphiregulin) compared with Tregs isolated from splenic tissue. Lastly, Tregs isolated from human lung tissue can be stimulated ex vivo to induce kgf expression. This study reveals mechanisms by which Tregs direct tissue-reparative effects during resolution after acute lung injury, further supporting the emerging role of Tregs in tissue repair.
Regulatory T cells, characterized by their expression of the transcription factor Forkhead box P3, are indispensable in maintaining immune homeostasis. The respiratory system is constantly exposed to ...many environmental challenges, making it susceptible to various insults and infections. Regulatory T cells play essential roles in maintaining homeostasis in the lung and promoting repair after injury. Regulatory T cell function dysregulation can lead to inflammation, tissue damage, or aberrant repair. Research on regulatory T cell mechanisms in the lung has unveiled their influence on lung inflammation and repair mechanisms. In this review, our goal is to highlight the advances in regulatory T cell biology with respect to lung injury and resolution. We further provide a perspective that a deeper understanding of regulatory T cell interactions in the lung microenvironment in health and disease states offers opportunities for therapeutic interventions as treatments to promote lung health.
•Regulatory T Cells.•Characterized by their expression of the transcription factor Forkhead box P3.•Maintain immune homeostasis and promote resolution after acute lung injury.•Dysregulation of functions may affect many lung disorders.
Thoroughly planned and implemented maintenance strategies save time and cost. However, the integration of maintenance work into reliability analysis is difficult as common modeling techniques are ...often not applicable due to state explosion which calls for restrictive model assumptions and oversimplification. From authors’ point of view, agent-based modeling (ABM) of technical and organizational systems is a promising approach to overcome such problems. But since ABM is not well established in reliability analysis its feasibility in this area still has to be demonstrated. For this purpose ABM is compared with Markov chains, namely by analyzing the reliability of a maintained
n-unit system with dependent repair events, applying both modeling approaches. Although ABM and Markov chains lead to the same numerical results, the former points out the potentiality of an improved system state handling. This is demonstrated by extending the ABM with operators as additional “agents” featuring their location
(
x
;
y
)
availability (0;1) and different maintenance strategies. This extension highlights the capability of ABM to analyze complex emergent system behavior and allows a systematic refinement and optimization of the maintenance strategies.
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