Risk Factors for the Mortality of Patients With Coronavirus Disease 2019 Requiring Extracorporeal Membrane Oxygenation in a Non-Centralized Setting: A Nationwide Study.

BACKGROUND: Limited data are available on the mortality rates of patients receiving extracorporeal membrane oxygenation (ECMO) support for coronavirus disease 2019 (COVID-19). We aimed to analyze the relationship between COVID-19 and clinical outcomes for patients receiving ECMO. METHODS: We retrospectively investigated patients with COVID-19 pneumonia requiring ECMO in 19 hospitals across Korea from January 1, 2020 to August 31, 2021. The primary outcome was the 90-day mortality after ECMO initiation. We performed multivariate analysis using a logistic regression model to estimate the odds ratio (OR) of 90-day mortality. Survival differences were analyzed using the Kaplan-Meier (KM) method. RESULTS: Of 127 patients with COVID-19 pneumonia who received ECMO, 70 patients (55.1%) died within 90 days of ECMO initiation. The median age was 64 years, and 63% of patients were male. The incidence of ECMO was increased with age but was decreased after 70 years of age. However, the survival rate was decreased linearly with age. In multivariate analysis, age (OR, 1.048; 95% confidence interval [CI], 1.010-1.089; P = 0.014) and receipt of continuous renal replacement therapy (CRRT) (OR, 3.069; 95% CI, 1.312-7.180; P = 0.010) were significantly associated with an increased risk of 90-day mortality. KM curves showed significant differences in survival between groups according to age (65 years) (log-rank P = 0.021) and receipt of CRRT (log-rank P = 0.004). CONCLUSION: Older age and receipt of CRRT were associated with higher mortality rates among patients with COVID-19 who received ECMO.

Role of extracorporeal membrane oxygenation as a salvage therapy for liver transplantation recipients in a high-volume transplant center.

Extracorporeal membrane oxygenation (ECMO) has been used sporadically in adult orthotopic liver transplantation (OLT) recipients for the treatment of acute cardiopulmonary failure. This retrospective study aimed to identify OLT patients who would benefit from ECMO support. We reviewed 109 OLT patients who received ECMO support for more than 24 h from January 2007 to December 2020. Among the enrolled patients, 15 (13.8%) experienced 18 ECMO-related complications and 12 (11.0%) experienced ECMO reapplication after weaning during the same hospitalization period. The successful weaning rates were 50.98% in patients who received ECMO support during the peritransplantation period (0-30 days from transplantation) and 51.72% in patients who received ECMO support in the post-OLT period (more than 30 days after OLT); 24 (47.1%) and 23 (39.7%) patients survived until hospital discharge, respectively. The 109 enrolled OLT recipients who received ECMO support during the perioperative period had a 1-year survival rate of 42.6%. Multivariate analyses identified the following as significant and independent risk factors for in-hospital mortality: ECMO treatment prior to 2011 ( p = 0.04), septic shock as the indication for ECMO treatment ( p = 0.001), and a total bilirubin level of ≥5.0 mg/dl ( p = 0.02). The outcomes of adult OLT recipients with ECMO treatment were acceptable in terms of weaning success and survival until hospital discharge. This study confirmed that ECMO treatment for OLT recipients with septic shock and elevated bilirubin levels might be associated with a higher in-hospital mortality and demonstrated the importance of a multidisciplinary ECMO team approach.

DnaJ-induced miRNA-146a negatively regulates the expression of IL-8 in macrophages.

As a member of the damage-associated molecular patterns, heat shock proteins (HSPs) are widely recognized for their role in initiating innate immune responses. These highly conserved proteins are expressed ubiquitously in both prokaryotes and eukaryotes. In this study, our aim was to investigate how DnaJ, a HSP40 homolog derived from Pseudomonas aeruginosa (P. aeruginosa), influences the regulation of IL-8 expression in macrophages. Treatment with DnaJ served as a stimulus, inducing a more robust expression of IL-8 compared to other HSP homologs, including DnaK, GroEL, and HtpG. This effect was achieved through the activation of the NF-κB signaling pathway. Interestingly, DnaJ treatment also significantly increased the expression of microRNA-146a (miR-146a), which appears to play a role in modulating the expression of innate defense genes. As a consequence, pre-treatment with DnaJ led to a reduction in the extent of IL-8 induction in response to P. aeruginosa treatment. Notably, this reduction was counteracted by transfection of a miR-146a inhibitor, highlighting the involvement of miR-146a in P. aeruginosa-mediated induction of IL-8 expression. Therefore, this study uncovers the role of DnaJ in triggering the expression of miR-146a, which, in turn, modulates the excessive expression of IL-8 induced by P. aeruginosa infection.

False positive Aspergillus galactomannan assay results caused by specific parenteral nutrition.

In September 2022, the proportion of clinically false positive results with high index values for the galactomannan (GM) assay increased dramatically in our hospital and remained high until November 2022. We aimed to identify the possible causative agent that led to the dramatic increase in false positivity in GM assay. A case-control-control study was conducted, and patients admitted to two intensive care units between September and November 2022 were included. We defined each time point at which the GM assay was conducted in a patient as an episode and classified episodes into strong-positive (≥10.0 index; case), positive (control), and negative (<0.5 index; control) groups. We compared the medications administered in three groups and measured GM levels in relevant medications, including parenteral nutrition (PN). In total, 118 episodes in 33 patients were classified into three groups. There were 46 negative, 23 positive, and 49 strong-positive episodes, and there was a significant difference in the use of Winuf® PNs (P < .001) between the three groups. Forty episodes (82%) in the strong-positive group received Winuf®, compared with three (6.5%) in the negative group and one (4.3%) in the positive group (P < .001). All samples of Winuf® PNs used in the five patients whose GM results were repeatedly strong-positive were strongly positive for GM. False positivity in GM assay can be caused by the administration of specific PNs. A thorough investigation of prescribed medications should be considered when there is an abrupt increase in the proportion of strong-positive or positive GM results.

Pseudomonas aeruginosa-Derived DnaJ Induces the Expression of IL-1ß by Engaging the Interplay of p38 and ERK Signaling Pathways in Macrophages.

As members of pathogen-associated molecular patterns, bacterial heat shock proteins (HSPs) are widely recognized for their role in initiating innate immune responses. This study aimed to examine the impact of DnaJ, a homolog of HSP40 derived from Pseudomonas aeruginosa (P. aeruginosa), on the regulation of IL-1ß expression in macrophages. We demonstrated that DnaJ modulates macrophages to secrete IL-1ß by activating NF-κB and MAPK signaling pathways. Specifically, ERK was identified as a positive mediator for IL-1ß expression, while p38 acted as a negative mediator. These results suggest that the reciprocal actions of these two crucial MAPKs play a vital role in controlling IL-1ß expression. Additionally, the reciprocal actions of MAPKs were found to regulate the activation of inflammasome-related molecules, including vimentin, NLRP3, caspase-1, and GSDMD. Furthermore, our investigation explored the involvement of CD91/CD40 in ERK signaling-mediated IL-1ß production from DnaJ-treated macrophages. These findings emphasize the importance of understanding the signaling mechanisms underlying IL-1ß induction and suggest the potential utility of DnaJ as an adjuvant for stimulating inflammasome activation.

DnaJ-induced TLR7 mediates an increase in interferons through the TLR4-engaged AKT/NF-κB and JNK signaling pathways in macrophages.

Toll-like receptor 7 (TLR7) signaling plays pivotal roles in innate immunity by sensing viral single-stranded RNA thereby triggering inflammatory signaling cascades and eliciting protective antiviral responses. In this study, we found that TLR7 expression is highly induced in response to Pseudomonas aeruginosa (P. aeruginosa) infection in a dose- and time-dependent manner. P. aeruginosa-derived DnaJ, a homolog of HSP40, was identified as a related inducing agent for TLR7 expression, and expression of DnaJ was stimulated when host cells were infected with P. aeruginosa. Interestingly, DnaJ was not involved in mediating an increase in the expression levels of TLR3 and TLR8, other well-known antiviral receptors. The induction of TLR7 in response to DnaJ was mediated by the activation of the AKT (Thr308 and Ser473)/NF-κB and p38/JNK MAPKs signaling pathways, consequently transmitting related signals for the expression of interferons (IFNs). Of note, these antiviral responses were regulated, at least in part, by TLR4, which senses the presence of DnaJ and then promotes downstream activation of the AKT (Ser473)/NF-κB and JNK signaling cascades. Taken together, these results suggest that P. aeruginosa-derived DnaJ is sufficient to promote an increase in TLR7 expression in the TLR4-engaged AKT/NF-κB and JNK signaling pathways, thereby promoting an increased antiviral response through the elevated expression of IFNs.

Attributable mortality of acute respiratory distress syndrome: a systematic review, meta-analysis and survival analysis using targeted minimum loss-based estimation.

BACKGROUND: Although acute respiratory distress syndrome (ARDS) is associated with high mortality, its direct causal link with death is unclear. Clarifying this link is important to justify costly research on prevention of ARDS. OBJECTIVE: To estimate the attributable mortality, if any, of ARDS. DESIGN: First, we performed a systematic review and meta-analysis of observational studies reporting mortality of critically ill patients with and without ARDS matched for underlying risk factor. Next, we conducted a survival analysis of prospectively collected patient-level data from subjects enrolled in three intensive care unit (ICU) cohorts to estimate the attributable mortality of critically ill septic patients with and without ARDS using a novel causal inference method. RESULTS: In the meta-analysis, 44 studies (47 cohorts) involving 56 081 critically ill patients were included. Mortality was higher in patients with versus without ARDS (risk ratio 2.48, 95% CI 1.86 to 3.30; p<0.001) with a numerically stronger association between ARDS and mortality in trauma than sepsis. In the survival analysis of three ICU cohorts enrolling 1203 critically ill patients, 658 septic patients were included. After controlling for confounders, ARDS was found to increase the mortality rate by 15% (95% CI 3% to 26%; p=0.015). Significant increases in mortality were seen for severe (23%, 95% CI 3% to 44%; p=0.028) and moderate (16%, 95% CI 2% to 31%; p=0.031), but not for mild ARDS. CONCLUSIONS: ARDS has a direct causal link with mortality. Our findings provide information about the extent to which continued funding of ARDS prevention trials has potential to impart survival benefit. PROSPERO REGISTRATION NUMBER: CRD42017078313.

Usefulness of ICU criteria for diagnosis of invasive pulmonary aspergillosis in nonhematologic critically ill patients.

Invasive pulmonary aspergillosis (IPA) is a life-threatening disease in the intensive care unit (ICU). The ICU criteria were proposed to diagnose IPA in critically ill patients. This study aims to evaluate the usefulness of ICU criteria for diagnosis and treatment of IPA in nonhematologic patients in the ICU. We retrospectively reviewed 103 ICU patients with positive galactomannan test in blood and respiratory tract from January 1, 2016, to May 31, 2017. We excluded patients with hematologic malignancy. We divided the treatment and non-treatment groups according to the IPA treatment. We compared the baseline characteristics and outcomes between two groups and the agreement with ICU criteria. There were 49 patients in treatment groups and 54 patients in non-treatment groups. There were more cases of solid organ transplantation (P = .003), immunosuppressive therapy (P < .001) and bacterial viral coinfection (P = .048) in the treatment group compared to nontreatment group. There was no statistically significant difference in mortality, the use of ventilator, and septic shock between the two groups. The agreement rate between the putative group and treatment was low (59.2%). There was no statistically significant difference in outcome between the putative and colonization groups according to the ICU criteria in each group. The treatment of IPA based on the symptom, radiologic finding and galactomannan test did not showed the better outcome. Also, the treatment based on the ICU criteria didn't show the difference of outcome. The new criteria for diagnosis of IPA in critically ill patients are needed.

Association Between Duration of Aminoglycoside Treatment and Outcome of Cavitary Mycobacterium avium Complex Lung Disease.

BACKGROUND: Although aminoglycosides are recommended for cavitary Mycobacterium avium complex lung disease (MAC-LD), the optimal duration of treatment is unclear. We investigated the association between duration of aminoglycoside treatment and outcomes in cavitary MAC-LD. METHODS: Among patients diagnosed with macrolide-susceptible cavitary MAC-LD between 2000 and 2013, 101 who received treatment up to August 2017 with a regimen containing aminoglycosides were enrolled at a tertiary referral center in South Korea. Their medical records were retrospectively reviewed. The duration of aminoglycoside treatment was at the discretion of the attending physician. RESULTS: A total of 75 patients (74.3%) were administered aminoglycosides for ≥3 months (median 164 days), whereas the remaining 26 patients (25.7%) received treatment for <3 months (median 59 days). The overall treatment success rate was 63.4% (64/101). Patients treated with aminoglycosides for ≥3 months had a significantly higher success rate than those treated for <3 months (69.3% vs 46.2%; P = .035). Multivariate analysis revealed that aminoglycoside treatment for ≥3 months was a significant factor for treatment success (adjusted odds ratio, 3.602; 95% confidence interval, 1.249-10.390; P = .018). Recurrence occurred in 8 (22.9%) of 35 patients who were followed up for at least 3 years after the end of treatment; all 8 patients received aminoglycosides for ≥3 months. CONCLUSIONS: Patients with cavitary MAC-LD treated with aminoglycosides for ≥3 months showed higher treatment success rate than those treated for <3 months. However, treatment for ≥3 months was not associated with the development of recurrence.

Central Extracorporeal Membrane Oxygenation for Bridging of Right-Sided Heart Failure to Lung Transplantation: A Single-Center Experience and Literature Review.

OBJECTIVE: Right-sided heart failure develops in lung transplantation candidates on prolonged peripheral extracorporeal membrane oxygenation support and is a major determinant of mortality. The use of central venoarterial extracorporeal membrane oxygenation for bridging of right-sided heart failure to lung transplantation was evaluated. DESIGN: Retrospective case series and literature review. SETTING: A single tertiary care university hospital. PARTICIPANTS: The study comprised lung transplantation candidates on extracorporeal membrane oxygenation bridging who developed right-sided heart failure. INTERVENTIONS: Central venoarterial extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS: Of 6 patients who underwent the study protocol, 3 were bridged successfully to lung transplantation and 1 was bridged to recovery. CONCLUSIONS: The study demonstrates that central extracorporeal membrane oxygenation may be a feasible option for bridging of right-sided heart failure to lung transplantation.

In Vitro MIC Values of Rifampin and Ethambutol and Treatment Outcome in Mycobacterium avium Complex Lung Disease.

Although it is known that the in vitro MICs of rifampin and ethambutol are poorly correlated with the clinical response in Mycobacterium avium complex (MAC) lung disease (MAC-LD), evidence for this is limited. This study investigated the association between treatment outcome and the in vitro MICs of rifampin and ethambutol in patients with MAC-LD. Among patients diagnosed with macrolide-susceptible MAC-LD between January 2008 and December 2013, 274 patients who were treated with a standard regimen for ≥12 months until August 2017 and whose in vitro MIC results were available were enrolled at a tertiary referral center in South Korea. The MICs of antimicrobial agents were determined using the broth microdilution method. The mean age of the included patients was 60.4 years. The overall treatment success rate was 79.6% (218/274 patients) and tended to decrease with increasing MICs of rifampin and ethambutol, particularly at MICs of ≥8 µg/ml. Treatment success rate was significantly different between MAC isolates with MICs of ≥8 µg/ml for rifampin and ethambutol and those with MICs of <8 µg/ml for rifampin and/or ethambutol (64.9% versus 85.3%, P < 0.001). Multivariate analysis showed that an MIC of ≥8 µg/ml for both drugs and initial sputum acid-fast bacillus (AFB) smear positivity were independent risk factors for an unfavorable response (adjusted odds ratio [OR] = 3.154, 95% confidence interval [CI] = 1.641 to 6.063, and P = 0.001 for an MIC of ≥8 µg/ml; adjusted OR = 2.769, 95% CI = 1.420 to 5.399, and P = 0.003 for initial sputum AFB smear positivity). These findings suggest that the in vitro MICs of rifampin and ethambutol may be related to treatment outcome in MAC-LD.

Effects of Corticosteroids on Critically Ill Pulmonary Tuberculosis Patients With Acute Respiratory Failure: A Propensity Analysis of Mortality.

BACKGROUND: We investigated the effects of corticosteroids on the 90-day mortality outcomes in patients with pulmonary tuberculosis who were admitted to the intensive care unit (ICU) because of acute respiratory failure (ARF). METHODS: The medical records of 124 patients who had pulmonary tuberculosis with ARF and were admitted to the ICU at our tertiary referral center in South Korea between March 1989 and December 2014 were retrospectively analyzed. The 90-day mortality rate in this population was analyzed after adjustments with the inverse probability of treatment weighted (IPTW) method. RESULTS: The mean patient age was 62 years, and the 90-day mortality rate was 49.2% (61/124). Adjuvant steroids were used in 70 (56.5%) patients. The 90-day mortality rate was similar irrespective of corticosteroid use (48.6%, steroid group; 50.0%, nonsteroid group). The use of adjuvant steroids was not associated with the unadjusted 90-day mortality (odds ratio [OR], 0.94; 95% confidence interval [CI], .46-1.92; P = .875). In a comparison using an adjusted IPTW approach of the 90-day mortality between the 2 groups, we found that corticosteroid use was independently associated with reduced 90-day mortality (OR, 0.47; 95% CI, .22-.98; P = .049). CONCLUSIONS: The study results showed that corticosteroids could reduce the 90-day mortality rate in critically ill pulmonary tuberculosis patients with ARF.

Different pattern of viral infections and clinical outcomes in patient with acute exacerbation of chronic obstructive pulmonary disease and chronic obstructive pulmonary disease with pneumonia.

Respiratory viruses are well-known causes of acute exacerbation of chronic obstructive pulmonary disease (AE-COPD) and also important pathogens for concomitant pneumonia in COPD (CP-COPD). However, the differences in a viral infection pattern and clinical impacts of respiratory viruses between the two groups have not been well investigated. The clinical and microbiological data from COPD patients admitted with AE-COPD (n = 281) or CP-COPD (n = 284) between January 2010 and December 2012 were reviewed. After excluding 88 patients (40 with AE-COPD and 48 with CP-COPD) who did not undergo a multiplex RT-PCR test for respiratory viruses, the demographic characteristics, identified viruses, and clinical outcomes of the AE-COPD and CP-COPD groups were compared. Respiratory viruses were identified in 41.9% of AE-COPD group and 33.5% of the CP-COPD groups. The most common virus was influenza virus in the AE-COPD group (33.7%) versus human coronavirus (24.1%) in the CP-COPD group. Influenza virus was significantly more common in the AE-ACOPD group than in the CP-COPD group (P < 0.01). In-hospital mortality of AE-COPD and CP-COPD were 1.2% and 12.3%, respectively (P < 0.01). Among CP-COPD patients, in-hospital mortality of patients with only viral infection group, only bacterial infection group, and viral-bacterial co-infection were 2.6%, 25.8%, and 17.5%, respectively (P = 0.01). Respiratory viruses were commonly identified in both AE-COPD and CP-COPD, influenza virus and human coronavirus were the most common viruses identified in AE-COPD and CP-COPD patients, respectively. The mortality rates of only viral infection group was significantly lower than only bacterial infection or viral-bacterial co-infection group in CP-COPD patients. J. Med. Virol. 88:2092-2099, 2016. © 2016 Wiley Periodicals, Inc.

Intratracheal administration of umbilical cord blood-derived mesenchymal stem cells in a patient with acute respiratory distress syndrome.

Umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) have been introduced as a possible therapy in acute lung injury and acute respiratory distress syndrome (ARDS). This case history is reported of a 59-yr-old man who was treated with MSCs in the course of ARDS and subsequent pulmonary fibrosis. He received a long period of mechanical ventilation and weaning proved difficult. On hospital day 114, he underwent the intratracheal administration of UCB-derived MSCs at a dose of 1 × 10(6)/kg. After cell infusion, an immediate improvement was shown in his mental status, his lung compliance (from 22.7 mL/cmH2O to 27.9 mL/cmH2O), PaO2/FiO2 ratio (from 191 mmHg to 334 mmHg) and his chest radiography over the course of three days. Even though he finally died of repeated pulmonary infection, our current findings suggest the possibility of using MSCs therapy in an ARDS patient. It is the first clinical case of UCB-derived MSCs therapy ever reported.

Ventilation parameters used to guide cardiopulmonary function during mechanical ventilation.

PURPOSE OF REVIEW: To describe the newly introduced ventilation parameters that are used at the bedside to estimate cardiopulmonary function during positive pressure ventilation (PPV). RECENT FINDINGS: PPV induces right atrial pressure changes over the ventilator cycle. Positive end-expiratory pressure-induced central venous pressure changes and pulse pressure variation have been introduced as parameters that predict fluid responsiveness. Pulse pressure variation seems to be valid even at low tidal volume ventilation. A capnometer can be used to measure low perfusion lung area and to monitor the continuous breath-by-breath cardiac output of ventilated patients. Ultrasound evaluation of the lung parenchyma and diaphragm status is likely to become more popular. To evaluate ventilator settings, functional residual capacity (FRC) measurement and visual lung recruitment estimation via electric impedance tomography (EIT) have been introduced. SUMMARY: The utility of lung ultrasound is expanding. Although the clinical implications of FRC measurement and lung monitoring with imaging tools such as EIT are starting to be realized, their efficacy in severe hypoxic respiratory failure should be evaluated further in well designed clinical trials. To improve the preemptive management of impending respiratory failure, an alarm index that integrates noninvasive cardiopulmonary function parameters should be developed.

The effectiveness of vitamin C for patients with severe viral pneumonia in respiratory failure.

BACKGROUND: Vitamin C is a well-known antioxidant and essential cofactor for numerous biological reactions. Several studies reported that vitamin C can improve the symptoms and prognosis of patients with sepsis and respiratory infection. We aimed to examine the effect of vitamin C when used in viral pneumonia patients with severe respiratory failure. METHODS: Total 201 patients with viral pneumonia were included, of them 35 patients used vitamin C. We performed a statistical analysis through a propensity score matching of the age and baseline characteristics of these patients. RESULTS: There were differences between the vitamin C group and non-vitamin C group in terms of age (60±15 vs. 66±14, P=0.03), extracorporeal membrane oxygenation (28.6% vs. 5.4%, P<0.001), and procalcitonin (3±8 vs. 9±23, P=0.02). The 28-day mortality was not different between the two groups (20.0% vs. 24.7%, P=0.33). In the propensity-matched group, the 28-day mortality was not significantly different between the two groups (20.0% vs. 37.1%, P=0.07). Moreover, no difference was observed in shock reversal within 14 days (45.7% vs. 25.7%, P=0.08) and recovery after acute kidney injury (52.9% vs. 66.7%, P=0.41) between the two groups. Vitamin C was not a prognostic factor for 28-day mortality (P=0.33). CONCLUSIONS: In this study adjunctive intravenous vitamin C therapy alone was not associated with improvement of the 28-day mortality and prognosis in patients with severe viral pneumonia with respiratory failure.

Over 500 Liver Transplants Including More Than 400 Living-Donor Liver Transplants in 2019 at Asan Medical Center.

BACKGROUND: More than 400 liver transplants were performed at Asan Medical Center (AMC) in 2011, and over 500 liver transplants including 420 living-donor liver transplants (LDLTs) were performed in 2019. Herein, we report the methodology of these procedures. METHODS: Since the first adult LDLTs at AMC using the left and right lobes were successfully performed, various innovative techniques and approaches have been developed: modified right lobe, dual graft, donor exchange for ABO incompatibility, expansion of indications and no-touch techniques for hepatocellular carcinoma, intraoperative cine-portogram and additional intervention for large collaterals, management of portal vein thrombosis (PVT) and stenosis, salvage LDLT after major hepatectomy, and timely LDLT for patients with acute-on-chronic liver failure. RESULTS: Four hundred twenty LDLTs in 403 adult and 17 pediatric patients and 85 deceased-donor liver transplants in 74 adult and 11 pediatric patients were performed. The number of deceased-donor liver transplants remained constant since 2011, but the number of LDLTs increased steadily. One hundred thirty patients (25.7%) required urgent liver transplantations and 24 patients with acute-on-chronic liver failure underwent LDLT. PVT including grade 1,2,3, and 4 was reported in 91 patients (18.0%), and Yerdel's grade 2, 3, and 4 PVT was reported in 47 patients (51.6%); all patients with PVT were successfully treated. Adult LDLTs for hepatocellular carcinoma and ABO incompatibility accounted for 52.6% and 24.3% of the cases, respectively. In-hospital mortality in 2019 was 2.97%. CONCLUSION: Continual efforts to overcome challenging problems in LDLT with various innovations and dedication of the team members during the perioperative period to improve patient outcomes were crucial in increasing the number of liver transplantations at Asan Medical Center.

The Pseudomonas aeruginosa HSP90-like protein HtpG regulates IL-8 expression through NF-κB/p38 MAPK and CYLD signaling triggered by TLR4 and CD91.

Pulmonary infection activates acute inflammatory responses by recruiting neutrophils to the infection site; this recruitment is promoted by interleukin-8 (IL-8). However, IL-8 production in response to Pseudomonas aeruginosa HtpG (PA1596), a homolog of heat shock protein 90, has yet not been characterized in detail. htpG expression in P. aeruginosa strain was elevated upon infection of host cells, and HtpG was released into bacterial culture supernatant. Treatment of dTHP-1 macrophages with recombinant HtpG (rHtpG) increased production of IL-8 in a dose- and time-dependent manner, and this effect was abolished by inhibition of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) p38 signaling. By contrast, the rHtpG-mediated production of IL-8 was increased by suppression of cylindromatosis (CYLD), suggesting that CYLD is a negative regulator of this pathway. The upregulation of expression was coordinated by signals transmitting through toll-like receptor 4 (TLR4) with the aid of CD91. Together, these observations suggest that P. aeruginosa HtpG activates NF-κB, CYLD, and p38 MAPK in a TLR4-and CD91-dependent manner, leading to stimulation of IL-8 production in macrophages.

Maackiain, a compound derived from Sophora flavescens, increases IL-1ß production by amplifying nigericin-mediated inflammasome activation.

Sophora flavescens is used as a traditional herbal medicine to modulate inflammatory responses. However, little is known about the impact of (-)-maackiain, a compound derived from S. flavescens, on the activation of inflammasome/caspase-1, a key factor in interleukin-1ß (IL-1ß) processing. Here, we report that (-)-maackiain potently amplified caspase-1 cleavage in macrophages in response to nigericin (Nig). In macrophages primed with either lipopolysaccharide or monophosphoryl lipid A, Nig-mediated caspase-1 cleavage was also markedly promoted by (-)-maackiain. Notably, (-)-maackiain induced the production of vimentin, an essential mediator for the activation of the NOD-, LRR-, and pyrin domain-containing protein 3 inflammasome, thereby contributing to promotion of the formation of the inflammasome complex to activate caspase-1. Taken together, our data suggest that (-)-maackiain exerts an immunostimulatory effect by promoting IL-1ß production via activation of the inflammasome/caspase-1 pathway. Thus, the potent inflammasome-activating effect of (-)-maackiain may be clinically useful as an acute immune-stimulating agent.