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The molecular mechanisms of acute lung injury resulting in inflammation and fibrosis are not well established. Here we investigate the roles of the IL-1 receptor 1 (IL-1R1) and the common adaptor for Toll/IL-1R signal transduction, MyD88, in this process using a murine model of acute pulmonary injury. Bleomycin insult results in expression of neutrophil and lymphocyte chemotactic factors, chronic inflammation, remodeling, and fibrosis. We demonstrate that these end points were attenuated in the lungs of IL-1R1- and MyD88-deficient mice. Further, in bone marrow chimera experiments, bleomycin-induced inflammation required primarily MyD88 signaling from radioresistant resident cells. Exogenous rIL-1beta recapitulated a high degree of bleomycin-induced lung pathology, and specific blockade of IL-1R1 by IL-1 receptor antagonist dramatically reduced bleomycin-induced inflammation. Finally, we found that lung IL-1beta production and inflammation in response to bleomycin required ASC, an inflammasome adaptor molecule. In conclusion, bleomycin-induced lung pathology required the inflammasome and IL-1R1/MyD88 signaling, and IL-1 represented a critical effector of pathology and therapeutic target of chronic lung inflammation and fibrosis.

The lung alveolar region experiences remodeling during several acute and chronic lung diseases, as for instance idiopathic pulmonary fibrosis (IPF), a fatal disease, whose onset is correlated with repetitive microinjuries to the lung alveolar epithelium and abnormal alveolar wound repair. Although a high degree of mechanical stress (>20% linear strain) is thought to potentially induce IPF, the effect of lower, physiological levels of strain (5-12% linear strain) on IPF pathophysiology remains unknown. In this study, we examined the influence of mechanical strain on alveolar epithelial wound healing. For this purpose, we adopted the \"organ-on-a-chip\" approach, which provides the possibility of reproducing unique aspects of the cellular microenvironment, in particular its dynamic nature. Our results provide the first demonstration that a wound healing assay can be performed on a breathing lung-on-a-chip equipped with an ultra-thin elastic membrane. We cultured lung alveolar epithelial cells to confluence, the cells were starved for 24 h, and then wounded by scratching with a standard micropipette tip. Wound healing was assessed after 24 h under different concentrations of recombinant human hepatic growth factor (rhHGF) and the application of cyclic mechanical stretch. Physiological cyclic mechanical stretch (10% linear strain, 0.2 Hz) significantly impaired the alveolar epithelial wound healing process relative to culture in static conditions. This impairment could be partially ameliorated by administration of rhHGF. This proof-of-concept study provides a way to study of more complex interactions, such as a co-culture with fibroblasts, endothelial cells, or immune cells, as well as the study of wound healing at an air-liquid interface.

Routine identification of pathogens by MALDI-TOF MS (matrix-assisted laser desorption ionisation time-of-flight mass spectrometry) is based on the fingerprint of intracellular proteins. This work evaluated the use of MALDI-TOF MS for the identification of extracellular pathogen factors. A Staphylococcus aureus isolate from a food contaminant was exponentially grown in liquid cultures. Secreted proteins were collected using methanol– chloroform precipitation and analysed by MALDI-TOF MS. A main peak m/z 28,250 was demonstrated, which was identified as S.aureus enterotoxin type B (SEB) by using the pure authentic SEB reference of 28.2 kDa and by amino acid sequence analysis. SEB was also detected in this intact form following pasteurization and cooking treatments. Further application of the elaborated MALDI-TOF MS protocol resulted in the detection of SEA at m/z 27,032 and SEC at m/z 27,629. In conclusion, a simple sample preparation from S.aureus cultures and an easy-to-perform identification of pathogen factors SE in intact form represents a promising next-generation application of MALDI-TOF MS.

Inhaled endotoxins induce an acute inflammatory response in the airways mediated through Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88). However, the relative roles of the TLR4 adaptor proteins TIRAP and TRIF and of the MyD88-dependent IL-1 and IL-18 receptor pathways in this response are unclear. Here, we demonstrate that endotoxin-induced acute bronchoconstriction, vascular damage resulting in protein leak, Th1 cytokine and chemokine secretion and neutrophil recruitment in the airways are abrogated in mice deficient for either TIRAP or MyD88, but not in TRIF deficient mice. The contribution of other TLR-independent, MyD88-dependent signaling pathways was investigated in IL-1R1, IL-18R and caspase-1 (ICE)-deficient mice, which displayed normal airway responses to endotoxin. In conclusion, the TLR4-mediated, bronchoconstriction and acute inflammatory lung pathology to inhaled endotoxin critically depend on the expression of both adaptor proteins, TIRAP and MyD88, suggesting cooperative roles, while TRIF, IL-1R1, IL-18R signaling pathways are dispensable.

Candida albicans frequently causes recurrent intimal infectious disease (ID). This demands the treatment of multiple phases of the infection. The objective of this study was to uncover the host–pathogen interaction using two-dimensional (2D) epithelium cell-barrier and three-dimensional (3D) subepithelium tissue cells of human mucosa. The 2D cell cultures assessed C. albicans adhesion. Addition of the antifungal drug Fluconazol did not inhibit the adhesion, despite its pathogen growth inhibition (minimal inhibitory concentration value 0.08 μg/mL). A 3D tissue was engineered in multitranswells by placing human fibroblast cultures on a thick porous scaffold. This contained the yeast placed in the top compartment and prevented passive penetration. After 28 h, the pathogen transmigrated the barrier and was collected in the bottom compartment. A change in pathogen morphology was observed where hypha formed and grew to be 231 μm long after 28 h. The hypha was thus long enough to cross the 200 μm thick 3D tissue. The 3D infection was inhibited by addition of Fluconazol (0.08 μg/mL), confirming that penetration is dependent on pathogen growth. In conclusion, ID was reconstituted step-by-step on 2D epithelium surface and in 3D connective tissue of human mucosa. Fluconazol growth-inhibition of the pathogen C. albicans was confirmed in the 3D tissue. We thus propose that this ID in vitro test is suitable for the identification and characterization of new treatments against C. albicans .

Routine identification of pathogens by MALDI-TOF MS (matrix-assisted laser desorption ionisation time-of-flight mass spectrometry) is based on the fingerprint of intracellular proteins. This work evaluated the use of MALDI-TOF MS for the identification of extracellular pathogen factors. A Staphylococcus aureus isolate from a food contaminant was exponentially grown in liquid cultures. Secreted proteins were collected using methanol⁻ chloroform precipitation and analysed by MALDI-TOF MS. A main peak m/z 28,250 was demonstrated, which was identified as S.aureus enterotoxin type B (SEB) by using the pure authentic SEB reference of 28.2 kDa and by amino acid sequence analysis. SEB was also detected in this intact form following pasteurization and cooking treatments. Further application of the elaborated MALDI-TOF MS protocol resulted in the detection of SEA at m/z 27,032 and SEC at m/z 27,629. In conclusion, a simple sample preparation from S.aureus cultures and an easy-to-perform identification of pathogen factors SE in intact form represents a promising next-generation application of MALDI-TOF MS.

Leukemia inhibitory factor (LIF) is induced in inflammation and likely plays a regulatory role. Using LIF-deficient mice (LIF−/−), we report here that endogenous LIF has a protective role in endotoxic shock and host defence. LIF−/− mice have heightened sensitivity to LPS in a LPS/D-galactosamine (D-Gal) sensitization model compared to wild-type mice (LIF+/+), enhanced thrombocytopenia and leukopenia, with increased hepatic necrosis, neutrophil sequestration in the lung and accelerated mortality. These findings correlated with 10-fold higher tumour necrosis factor-α (TNFα) and interleukin-6 (IL-6) serum levels and reduced IL-10 production in LIF−/− mice in response to LPS. Therefore, endogenous LIF attenuates the endotoxic shock response, enhances the expression of basal acute phase proteins and IL-10 production, which downregulates TNFα synthesis and release and thereby confers partial protection to endotoxemia.

We present here the whole shotgun genome sequences of seven strains of Bacillus cereus isolated from foodstuff samples or food poisoning incidents.

Leukocyte adhesion molecules are involved in cell recruitment in an allergic airway response and therefore provide a target for pharmaceutical intervention. Neutrophil inhibitory factor (NIF), derived from canine hookworm ( Ancylostoma caninum ), binds selectively and competes with the A-domain of CD11b for binding to ICAM-1. The effect of recombinant NIF was investigated. Intranasal administration of rNIF reduced pulmonary eosinophilic infiltration, goblet cell hyperplasia, and Th 2 cytokine production in OVA-sensitized mice. In vitro , transendothelial migration of human blood eosinophils across IL-4-activated umbilical vein endothelial cell (HUVEC) monolayers was inhibited by rNIF (IC 50 : 4.6 ± 2.6 nM; mean ± SEM), but not across TNF or IL-1-activated HUVEC monolayers. Treatment of eosinophils with rNIF together with mAb 60.1 directed against CD11b or mAb 107 directed against the metal ion-dependent adhesion site (MIDAS) of the CD11b A-domain resulted in no further inhibition of transendothelial migration suggesting shared functional epitopes. In contrast, rNIF increased the inhibitory effect of blocking mAbs against CD18, CD11a, and VLA-4. Together, we show that rNIF, a selective antagonist of the A-domain of CD11b, has a prominent inhibitory effect on eosinophil transendothelial migration in vitro , which is congruent to the in vivo inhibition of OVA-induced allergic lung inflammation.

Background: The mental health impact of the COVID-19 crisis may differ from previously studied stressful events in terms of psychological reactions, specific risk factors, and symptom severity across geographic regions worldwide.Objective: To assess the impact of COVID-19 on a wide range of mental health symptoms, to identify relevant risk factors, to identify the effect of COVID-19 country impact on mental health, and to evaluate regional differences in psychological responses to COVID-19 compared to other stressful events.Method: 7034 respondents (74% female) participated in the worldwide Global Psychotrauma Screen - Cross-Cultural responses to COVID-19 study (GPS-CCC), reporting on mental health symptoms related to COVID-19 (n = 1838) or other stressful events (n = 5196) from April to November 2020.Results: Events related to COVID-19 were associated with more mental health symptoms compared to other stressful events, especially symptoms of PTSD, anxiety, depression, insomnia, and dissociation. Lack of social support, psychiatric history, childhood trauma, additional stressful events in the past month, and low resilience predicted more mental health problems for COVID-19 and other stressful events. Higher COVID-19 country impact was associated with increased mental health impact of both COVID-19 and other stressful events. Analysis of differences across geographic regions revealed that in Latin America more mental health symptoms were reported for COVID-19 related events versus other stressful events, while the opposite pattern was seen in North America.Conclusions: The mental health impact of COVID-19-related stressors covers a wide range of symptoms and is more severe than that of other stressful events. This difference was especially apparent in Latin America. The findings underscore the need for global screening for a wide range of mental health problems as part of a public health approach, allowing for targeted prevention and intervention programs. In a large global sample, COVID-19 was associated with more severe mental health symptoms compared to other stressful or traumatic events. The impact of COVID-19 on mental health differed around the world with an especially large impact in Latin America.