Dynamic lung aeration and strain with positive end-expiratory pressure individualized to maximal compliance versus ARDSNet low-stretch strategy: a study in a surfactant depletion model of lung injury.

BACKGROUND: Positive end-expiratory pressure (PEEP) individualized to a maximal respiratory system compliance directly implies minimal driving pressures with potential outcome benefits, yet, raises concerns on static and dynamic overinflation, strain and cyclic recruitment. Detailed accurate assessment and understanding of these has been hampered by methodological limitations. We aimed to investigate the effects of a maximal compliance-guided PEEP strategy on dynamic lung aeration, strain and tidal recruitment using current four-dimensional computed tomography (CT) techniques and analytical methods of tissue deformation in a surfactant depletion experimental model of acute respiratory distress syndrome (ARDS). METHODS: ARDS was induced by saline lung lavage in anesthetized and mechanically ventilated healthy sheep (n = 6). Animals were ventilated in a random sequence with: (1) ARDSNet low-stretch protocol; (2) maximal compliance PEEP strategy. Lung aeration, strain and tidal recruitment were acquired with whole-lung respiratory-gated high-resolution CT and quantified using registration-based techniques. RESULTS: Relative to the ARDSNet low-stretch protocol, the maximal compliance PEEP strategy resulted in: (1) improved dynamic whole-lung aeration at end-expiration (0.456 ± 0.064 vs. 0.377 ± 0.101, P = 0.019) and end-inspiration (0.514 ± 0.079 vs. 0.446 ± 0.083, P = 0.012) with reduced non-aerated and increased normally-aerated lung mass without associated hyperinflation; (2) decreased aeration heterogeneity at end-expiration (coefficient of variation: 0.498 ± 0.078 vs. 0.711 ± 0.207, P = 0.025) and end-inspiration (0.419 ± 0.135 vs. 0.580 ± 0.108, P = 0.014) with higher aeration in dorsal regions; (3) tidal aeration with larger inspiratory increases in normally-aerated and decreases in poorly-aerated areas, and negligible in hyperinflated lung (Aeration × Strategy: P = 0.026); (4) reduced tidal strains in lung regions with normal-aeration (Aeration × Strategy: P = 0.047) and improved regional distributions with lower tidal strains in middle and ventral lung (Region-of-interest [ROI] × Strategy: P < 0.001); and (5) less tidal recruitment in middle and dorsal lung (ROI × Strategy: P = 0.044) directly related to whole-lung tidal strain (r = 0.751, P = 0.007). CONCLUSIONS: In well-recruitable ARDS models, a maximal compliance PEEP strategy improved end-expiratory/inspiratory whole-lung aeration and its homogeneity without overinflation. It further reduced dynamic strain in middle-ventral regions and tidal recruitment in middle-dorsal areas. These findings suggest the maximal compliance strategy minimizing whole-lung dynamically quantified mechanisms of ventilator-induced lung injury with less cyclic recruitment and no additional overinflation in large heterogeneously expanded and recruitable lungs.

Analysis and validation of diagnostic biomarkers and immune cell infiltration characteristics in pediatric sepsis by integrating bioinformatics and machine learning.

BACKGROUND: Pediatric sepsis is a complicated condition characterized by life-threatening organ failure resulting from a dysregulated host response to infection in children. It is associated with high rates of morbidity and mortality, and rapid detection and administration of antimicrobials have been emphasized. The objective of this study was to evaluate the diagnostic biomarkers of pediatric sepsis and the function of immune cell infiltration in the development of this illness. METHODS: Three gene expression datasets were available from the Gene Expression Omnibus collection. First, the differentially expressed genes (DEGs) were found with the use of the R program, and then gene set enrichment analysis was carried out. Subsequently, the DEGs were combined with the major module genes chosen using the weighted gene co-expression network. The hub genes were identified by the use of three machine-learning algorithms: random forest, support vector machine-recursive feature elimination, and least absolute shrinkage and selection operator. The receiver operating characteristic curve and nomogram model were used to verify the discrimination and efficacy of the hub genes. In addition, the inflammatory and immune status of pediatric sepsis was assessed using cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT). The relationship between the diagnostic markers and infiltrating immune cells was further studied. RESULTS: Overall, after overlapping key module genes and DEGs, we detected 402 overlapping genes. As pediatric sepsis diagnostic indicators, CYSTM1 (AUC = 0.988), MMP8 (AUC = 0.973), and CD177 (AUC = 0.986) were investigated and demonstrated statistically significant differences (P < 0.05) and diagnostic efficacy in the validation set. As indicated by the immune cell infiltration analysis, multiple immune cells may be involved in the development of pediatric sepsis. Additionally, all diagnostic characteristics may correlate with immune cells to varying degrees. CONCLUSIONS: The candidate hub genes (CD177, CYSTM1, and MMP8) were identified, and the nomogram was constructed for pediatric sepsis diagnosis. Our study could provide potential peripheral blood diagnostic candidate genes for pediatric sepsis patients.

Macrophage ferroportin serves as a therapeutic target against bacteria-induced acute lung injury by promoting barrier restoration.

Acute respiratory distress syndrome (ARDS) is a common lung disorder that involves severe inflammatory damage in the pulmonary barrier, but the underlying mechanisms remain elusive. Here, we demonstrated that pulmonary macrophages originating from ARDS patients and mice caused by bacteria were characterized by increased expression of ferroportin (FPN). Specifically deleting FPN in myeloid cells conferred significant resistance to bacterial infection with improved survival by decreasing extracellular bacterial growth and preserving pulmonary barrier integrity in mice. Mechanistically, macrophage FPN deficiency not only limited the availability of iron to bacteria, but also promoted tissue restoration via growth factor amphiregulin, which is regulated by cellular iron-activated Yes-associated protein signaling. Furthermore, pharmacological treatment with C-Hep, the self-assembled N-terminally cholesterylated minihepcidin that functions in the degradation of macrophage FPN, protected against bacteria-induced lung injury. Therefore, therapeutic strategies targeting the hepcidin-FPN axis in macrophages may be promising for the clinical treatment of acute lung injury.

Proteomics of lung tissue reveals differences in inflammation and alveolar-capillary barrier response between atelectasis and aerated regions.

Atelectasis is a frequent clinical condition, yet knowledge is limited and controversial on its biological contribution towards lung injury. We assessed the regional proteomics of atelectatic versus normally-aerated lung tissue to test the hypothesis that immune and alveolar-capillary barrier functions are compromised by purely atelectasis and dysregulated by additional systemic inflammation (lipopolysaccharide, LPS). Without LPS, 130 proteins were differentially abundant in atelectasis versus aerated lung, mostly (n = 126) with less abundance together with negatively enriched processes in immune, endothelial and epithelial function, and Hippo signaling pathway. Instead, LPS-exposed atelectasis produced 174 differentially abundant proteins, mostly (n = 108) increased including acute lung injury marker RAGE and chemokine CCL5. Functional analysis indicated enhanced leukocyte processes and negatively enriched cell-matrix adhesion and cell junction assembly with LPS. Additionally, extracellular matrix organization and TGF-ß signaling were negatively enriched in atelectasis with decreased adhesive glycoprotein THBS1 regardless of LPS. Concordance of a subset of transcriptomics and proteomics revealed overlap of leukocyte-related gene-protein pairs and processes. Together, proteomics of exclusively atelectasis indicates decreased immune response, which converts into an increased response with LPS. Alveolar-capillary barrier function-related proteomics response is down-regulated in atelectasis irrespective of LPS. Specific proteomics signatures suggest biological mechanistic and therapeutic targets for atelectasis-associated lung injury.

Novel biomarkers for acute respiratory distress syndrome: genetics, epigenetics and transcriptomics.

Acute respiratory distress syndrome (ARDS) can be induced by multiple clinical factors, including sepsis, acute pancreatitis, trauma, intestinal ischemia/reperfusion and burns. However, these factors alone may poorly explain the risk and outcomes of ARDS. Emerging evidence suggests that genomic-based or transcriptomic-based biomarkers may hold the promise to establish predictive or prognostic stratification methods for ARDS, and also to help in the development of novel therapeutic targets for ARDS. Notably, genetic/epigenetic variations correlated with susceptibility and prognosis of ARDS and circulating microRNAs have emerged as potential biomarkers for diagnosis or prognosis of ARDS. Although limited by sample size, ethnicity and phenotypic heterogeneity, ongoing genetic/transcriptomic research contributes to the characterization of novel biomarkers and ultimately helps to develop innovative therapeutics for ARDS patients.

Plain language summary As the severe form of lung injury, acute respiratory distress syndrome (ARDS) affects about 10% of patients in intensive care units and causes 30­40% of deaths. ARDS can be induced by multiple clinical factors, including sepsis, severe pancreatitis, trauma, intestinal ischemia/reperfusion and burns. Early identification of those with high risk of ARDS would increase diagnostic efficiency and further improve outcomes of patients. Here, we review the most recent evidence that supports the roles of various biomarkers in predicting ARDS risk and outcome. Ongoing research contributes to the characterization of novel biomarkers and ultimately helps to develop innovative and more tailored therapeutics for ARDS patients.

Perioperative Pulmonary Atelectasis: Part II. Clinical Implications.

The development of pulmonary atelectasis is common in the surgical patient. Pulmonary atelectasis can cause various degrees of gas exchange and respiratory mechanics impairment during and after surgery. In its most serious presentations, lung collapse could contribute to postoperative respiratory insufficiency, pneumonia, and worse overall clinical outcomes. A specific risk assessment is critical to allow clinicians to optimally choose the anesthetic technique, prepare appropriate monitoring, adapt the perioperative plan, and ensure the patient's safety. Bedside diagnosis and management have benefited from recent imaging advancements such as lung ultrasound and electrical impedance tomography, and monitoring such as esophageal manometry. Therapeutic management includes a broad range of interventions aimed at promoting lung recruitment. During general anesthesia, these strategies have consistently demonstrated their effectiveness in improving intraoperative oxygenation and respiratory compliance. Yet these same intraoperative strategies may fail to affect additional postoperative pulmonary outcomes. Specific attention to the postoperative period may be key for such outcome impact of lung expansion. Interventions such as noninvasive positive pressure ventilatory support may be beneficial in specific patients at high risk for pulmonary atelectasis (e.g., obese) or those with clinical presentations consistent with lung collapse (e.g., postoperative hypoxemia after abdominal and cardiothoracic surgeries). Preoperative interventions may open new opportunities to minimize perioperative lung collapse and prevent pulmonary complications. Knowledge of pathophysiologic mechanisms of atelectasis and their consequences in the healthy and diseased lung should provide the basis for current practice and help to stratify and match the intensity of selected interventions to clinical conditions.

Perioperative Pulmonary Atelectasis: Part I. Biology and Mechanisms.

Pulmonary atelectasis is common in the perioperative period. Physiologically, it is produced when collapsing forces derived from positive pleural pressure and surface tension overcome expanding forces from alveolar pressure and parenchymal tethering. Atelectasis impairs blood oxygenation and reduces lung compliance. It is increasingly recognized that it can also induce local tissue biologic responses, such as inflammation, local immune dysfunction, and damage of the alveolar-capillary barrier, with potential loss of lung fluid clearance, increased lung protein permeability, and susceptibility to infection, factors that can initiate or exaggerate lung injury. Mechanical ventilation of a heterogeneously aerated lung (e.g., in the presence of atelectatic lung tissue) involves biomechanical processes that may precipitate further lung damage: concentration of mechanical forces, propagation of gas-liquid interfaces, and remote overdistension. Knowledge of such pathophysiologic mechanisms of atelectasis and their consequences in the healthy and diseased lung should guide optimal clinical management.

Lung Atelectasis Promotes Immune and Barrier Dysfunction as Revealed by Transcriptome Sequencing in Female Sheep.

BACKGROUND: Pulmonary atelectasis is frequent in clinical settings. Yet there is limited mechanistic understanding and substantial clinical and biologic controversy on its consequences. The authors hypothesize that atelectasis produces local transcriptomic changes related to immunity and alveolar-capillary barrier function conducive to lung injury and further exacerbated by systemic inflammation. METHODS: Female sheep underwent unilateral lung atelectasis using a left bronchial blocker and thoracotomy while the right lung was ventilated, with (n = 6) or without (n = 6) systemic lipopolysaccharide infusion. Computed tomography guided samples were harvested for NextGen RNA sequencing from atelectatic and aerated lung regions. The Wald test was used to detect differential gene expression as an absolute fold change greater than 1.5 and adjusted P value (Benjamini-Hochberg) less than 0.05. Functional analysis was performed by gene set enrichment analysis. RESULTS: Lipopolysaccharide-unexposed atelectatic versus aerated regions presented 2,363 differentially expressed genes. Lipopolysaccharide exposure induced 3,767 differentially expressed genes in atelectatic lungs but only 1,197 genes in aerated lungs relative to the corresponding lipopolysaccharide-unexposed tissues. Gene set enrichment for immune response in atelectasis versus aerated tissues yielded negative normalized enrichment scores without lipopolysaccharide (less than -1.23, adjusted P value less than 0.05) but positive scores with lipopolysaccharide (greater than 1.33, adjusted P value less than 0.05). Leukocyte-related processes (e.g., leukocyte migration, activation, and mediated immunity) were enhanced in lipopolysaccharide-exposed atelectasis partly through interferon-stimulated genes. Furthermore, atelectasis was associated with negatively enriched gene sets involving alveolar-capillary barrier function irrespective of lipopolysaccharide (normalized enrichment scores less than -1.35, adjusted P value less than 0.05). Yes-associated protein signaling was dysregulated with lower nuclear distribution in atelectatic versus aerated lung (lipopolysaccharide-unexposed: 10.0 ± 4.2 versus 13.4 ± 4.2 arbitrary units, lipopolysaccharide-exposed: 8.1 ± 2.0 versus 11.3 ± 2.4 arbitrary units, effect of lung aeration, P = 0.003). CONCLUSIONS: Atelectasis dysregulates the local pulmonary transcriptome with negatively enriched immune response and alveolar-capillary barrier function. Systemic lipopolysaccharide converts the transcriptomic immune response into positive enrichment but does not affect local barrier function transcriptomics. Interferon-stimulated genes and Yes-associated protein might be novel candidate targets for atelectasis-associated injury.

Inflammatory Activity in Atelectatic and Normally Aerated Regions During Early Acute Lung Injury.

RATIONALE AND OBJECTIVES: Pulmonary atelectasis presumably promotes and facilitates lung injury. However, data are limited on its direct and remote relation to inflammation. We aimed to assess regional 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) kinetics representative of inflammation in atelectatic and normally aerated regions in models of early lung injury. MATERIALS AND METHODS: We studied supine sheep in four groups: Permissive Atelectasis (n = 6)-16 hours protective tidal volume (VT) and zero positive end-expiratory pressure; Mild (n = 5) and Moderate Endotoxemia (n = 6)- 20-24 hours protective ventilation and intravenous lipopolysaccharide (Mild = 2.5 and Moderate = 10.0 ng/kg/min), and Surfactant Depletion (n = 6)-saline lung lavage and 4 hours high VT. Measurements performed immediately after anesthesia induction served as controls (n = 8). Atelectasis was defined as regions of gas fraction <0.1 in transmission or computed tomography scans. 18F-FDG kinetics measured with positron emission tomography were analyzed with a three-compartment model. RESULTS: 18F-FDG net uptake rate in atelectatic tissue was larger during Moderate Endotoxemia (0.0092 ± 0.0019/min) than controls (0.0051 ± 0.0014/min, p = 0.01). 18F-FDG phosphorylation rate in atelectatic tissue was larger in both endotoxemia groups (0.0287 ± 0.0075/min) than controls (0.0198 ± 0.0039/min, p = 0.05) while the 18F-FDG volume of distribution was not significantly different among groups. Additionally, normally aerated regions showed larger 18F-FDG uptake during Permissive Atelectasis (0.0031 ± 0.0005/min, p < 0.01), Mild (0.0028 ± 0.0006/min, p = 0.04), and Moderate Endotoxemia (0.0039 ± 0.0005/min, p < 0.01) than controls (0.0020 ± 0.0003/min). CONCLUSION: Atelectatic regions present increased metabolic activation during moderate endotoxemia mostly due to increased 18F-FDG phosphorylation, indicative of increased cellular metabolic activation. Increased 18F-FDG uptake in normally aerated regions during permissive atelectasis suggests an injurious remote effect of atelectasis even with protective tidal volumes.

Airway Epithelial Hepcidin Coordinates Lung Macrophages and Immunity Against Bacterial Pneumonia.

BACKGROUND: Hepcidin is a liver-derived master regulator of iron metabolism through its molecular target ferroportin, the only known mammalian iron exporter. Accumulated evidence has shown the important roles of hepatic hepcidin in host defense and infections. Hepcidin is also expressed by airway epithelial cells. However, the function of epithelial hepcidin during bacterial pneumonia remains unknown. METHODS: Pneumonia was induced in hepcidin-1-deficient and wild-type mice using the most common bacterial agents, and the effects of hepcidin on survival, bacterial burden, iron status, and macrophage phagocytosis after bacterial pneumonia were assessed. RESULTS: Hepcidin levels decreased in airway epithelium during common pneumonia, while lung macrophage-derived ferroportin levels and pulmonary iron concentrations increased. Lack of hepcidin in the airway epithelium worsened the outcomes of pneumonia. Manipulation of hepcidin level in the airway epithelium in mice with macrophage-specific ferroportin deletion did not affect the progress of pneumonia. Increased pulmonary iron concentration not only facilitated bacterial growth but also led to the defective phagocytic function of lung macrophages via activation of RhoA GTPase through oxidation of RhoGDI. Furthermore, enhancing the hepcidin level in the airway epithelium rescued mice from lethal bacterial pneumonia. CONCLUSIONS: These findings identify an uncharacterized important role of airway epithelial hepcidin in protection against bacterial pneumonia and provide the basis for novel alternative therapeutic strategies for combatting bacterial pneumonia in future translational research.

Increased gene copy number of DEFA1/DEFA3 worsens sepsis by inducing endothelial pyroptosis.

Sepsis claims an estimated 30 million episodes and 6 million deaths per year, and treatment options are rather limited. Human neutrophil peptides 1-3 (HNP1-3) are the most abundant neutrophil granule proteins but their neutrophil content varies because of unusually extensive gene copy number polymorphism. A genetic association study found that increased copy number of the HNP-encoding gene DEFA1/DEFA3 is a risk factor for organ dysfunction during sepsis development. However, direct experimental evidence demonstrating that these risk alleles are pathogenic for sepsis is lacking because the genes are present only in some primates and humans. Here, we generate DEFA1/DEFA3 transgenic mice with neutrophil-specific expression of the peptides. We show that mice with high copy number of DEFA1/DEFA3 genes have more severe sepsis-related vital organ damage and mortality than mice with low copy number of DEFA1/DEFA3 or wild-type mice, resulting from more severe endothelial barrier dysfunction and endothelial cell pyroptosis after sepsis challenge. Mechanistically, HNP-1 induces endothelial cell pyroptosis via P2X7 receptor-mediating canonical caspase-1 activation in a NLRP3 inflammasome-dependent manner. Based on these findings, we engineered a monoclonal antibody against HNP-1 to block the interaction with P2X7 and found that the blocking antibody protected mice carrying high copy number of DEFA1/DEFA3 from lethal sepsis. We thus demonstrate that DEFA1/DEFA3 copy number variation strongly modulates sepsis development in vivo and explore a paradigm for the precision treatment of sepsis tailored by individual genetic information.

Deterioration of Regional Lung Strain and Inflammation during Early Lung Injury.

RATIONALE: The contribution of aeration heterogeneity to lung injury during early mechanical ventilation of uninjured lungs is unknown. OBJECTIVES: To test the hypotheses that a strategy consistent with clinical practice does not protect from worsening in lung strains during the first 24 hours of ventilation of initially normal lungs exposed to mild systemic endotoxemia in supine versus prone position, and that local neutrophilic inflammation is associated with local strain and blood volume at global strains below a proposed injurious threshold. METHODS: Voxel-level aeration and tidal strain were assessed by computed tomography in sheep ventilated with low Vt and positive end-expiratory pressure while receiving intravenous endotoxin. Regional inflammation and blood volume were estimated from 2-deoxy-2-[(18)F]fluoro-d-glucose (18F-FDG) positron emission tomography. MEASUREMENTS AND MAIN RESULTS: Spatial heterogeneity of aeration and strain increased only in supine lungs (P < 0.001), with higher strains and atelectasis than prone at 24 hours. Absolute strains were lower than those considered globally injurious. Strains redistributed to higher aeration areas as lung injury progressed in supine lungs. At 24 hours, tissue-normalized 18F-FDG uptake increased more in atelectatic and moderately high-aeration regions (>70%) than in normally aerated regions (P < 0.01), with differential mechanistically relevant regional gene expression. 18F-FDG phosphorylation rate was associated with strain and blood volume. Imaging findings were confirmed in ventilated patients with sepsis. CONCLUSIONS: Mechanical ventilation consistent with clinical practice did not generate excessive regional strain in heterogeneously aerated supine lungs. However, it allowed worsening of spatial strain distribution in these lungs, associated with increased inflammation. Our results support the implementation of early aeration homogenization in normal lungs.

Hepatic hepcidin protects against polymicrobial sepsis in mice by regulating host iron status.

BACKGROUND: Hepcidin is a master regulator of iron metabolism primarily produced by the liver. Markedly increased hepcidin levels have been observed in septic individuals, while decreased hepatic hepcidin expression has been demonstrated in liver diseases that tend to develop into sepsis. However, the role of liver hepcidin in sepsis remains unknown. METHODS: Mouse hepatic hepcidin expression was silenced using adenovirus-mediated hepcidin-specific short hairpin RNA injected via the tail vein. Sepsis was induced by cecal ligation and puncture, and the outcome (n = 23 for hepcidin knockdown mice, n = 15 for controls) and pathogenic changes (n = 5) related to sepsis were evaluated. The impact of alteration of iron status on the survival rate of hepatic hepcidin knockdown mice (n = 18 to 19) was also investigated. RESULTS: Disruption of liver hepcidin expression increased serum iron level (537.8 ± 28.1 µg/dl [mean ± SD] vs. 235.9 ± 62.2 µg/dl; P < 0.05) and reduced iron content in the spleen macrophages at the steady state. Hepatic hepcidin knockdown mice not only showed increased 7-day mortality (73.9% vs. 46.7%; P < 0.05), but also had exacerbated organ damage and oxidative stress, as well as compromised host inflammatory responses and bacterial clearance at 24 h after polymicrobial sepsis. Treating the hepatic hepcidin knockdown mice with low-iron diet plus iron chelation decreased systemic iron content (serum level: 324.0 ± 67.4 µg/dl vs. 517.4 ± 13.4 µg/dl; P < 0.05) and rescued the mice from lethal sepsis (7-day survival: 36.8% vs. 83.3%; P < 0.01). CONCLUSIONS: Hepatic hepcidin plays an important role in sepsis through regulation of iron metabolism. The findings may have potential therapeutic implications for liver diseases in which hepcidin expression is decreased.

Activation of triggering receptor expressed on myeloid cells-1 protects monocyte from apoptosis through regulation of myeloid cell leukemia-1.

BACKGROUND: Triggering receptor expressed on myeloid cells-1 (TREM-1) can amplify the proinflammatory response and may contribute to the pathogenesis of inflammatory disease such as sepsis. However, the role of TREM-1 in monocyte fate and the detailed molecular mechanisms evoked by TREM-1 are unknown. METHODS: Adenoviruses overexpressing TREM-1 were constructed and transfected into a monocytic cell line. After activation of TREM-1 by agonist antibody with or without lipopolysaccharide, apoptosis was induced and assayed using flow cytometry. The signaling pathways downstream of TREM-1 were illustrated by inhibitory experiments. Proapoptotic/antiapoptotic protein levels were measured using immunoblot. In addition, the relationship between the expression levels of TREM-1 in monocytes and the magnitude of monocyte apoptosis were analyzed in septic patients. RESULTS: Activation of TREM-1 protected monocytes from staurosporine-induced apoptosis. This characteristic was also obtained under lipopolysaccharide stimulation. The protection of TREM-1 against monocyte apoptosis was abrogated after inhibition of extracellular signal-regulated kinase or v-akt murine thymoma viral oncogene homologue signaling. Cross-linking of TREM-1 remarkably up-regulated myeloid cell leukemia-1 protein level, and inhibition of extracellular signal-regulated kinase or v-akt murine thymoma viral oncogene homologue resulted in the reduction of myeloid cell leukemia-1 expression. Inhibition of myeloid cell leukemia-1 abolished the antiapoptotic effect of TREM-1. Furthermore, in septic patients, TREM-1 levels were inversely correlated to the magnitude of apoptosis in monocyte. CONCLUSIONS: TREM-1 played an important role in apoptosis in monocytes. Activation of TREM-1 protected monocytic cells from apoptosis through activation of both extracellular signal-regulated kinase and v-akt murine thymoma viral oncogene homologue pathways and increased expression of myeloid cell leukemia-1 protein. These findings provide a novel additional mechanism for TREM-1-mediated hyperinflammatory response in monocytes.