scholarly journals A Dual Role for the Plasminogen Activator Protease During the Preinflammatory Phase of Primary Pneumonic Plague

2020 ◽  
Vol 222 (3) ◽  
pp. 407-416 ◽  
Author(s):  
Srijon K Banerjee ◽  
Samantha D Crane ◽  
Roger D Pechous
Keyword(s):  
Plasminogen Activator ◽  
Pulmonary Infection ◽  
Bacterial Resistance ◽  
Inflammatory Responses ◽  
Dual Role ◽  
Bacterial Killing ◽  
Disease Symptoms ◽  
Unknown Mechanism ◽  
Pneumonic Plague ◽  
Neutrophil Influx

Abstract Early after inhalation, Yersinia pestis replicates to high numbers in the airways in the absence of disease symptoms or notable inflammatory responses to cause primary pneumonic plague. The plasminogen activator protease (Pla) is a critical Y. pestis virulence factor that is important for early bacterial growth in the lung via an unknown mechanism. In this article, we define a dual role for Pla in the initial stages of pulmonary infection. We show that Pla functions as an adhesin independent of its proteolytic function to suppress early neutrophil influx into the lungs, and that Pla enzymatic activity contributes to bacterial resistance to neutrophil-mediated bacterial killing. Our results suggest that the fate of Y. pestis infection of the lung is decided extremely early during infection and that Pla plays a dual role to tilt the balance in favor of the pathogen.

scholarly journals AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nathaniel B. Bone ◽  
Eugene J. Becker ◽  
Maroof Husain ◽  
Shaoning Jiang ◽  
Anna A. Zmijewska ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Pathogenic Bacteria ◽  
Inflammatory Responses ◽  
Abdominal Sepsis ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Lung Infections ◽  
Sepsis Survivors ◽  
The Impact

AbstractMetabolic and bioenergetic plasticity of immune cells is essential for optimal responses to bacterial infections. AMPK and Parkin ubiquitin ligase are known to regulate mitochondrial quality control mitophagy that prevents unwanted inflammatory responses. However, it is not known if this evolutionarily conserved mechanism has been coopted by the host immune defense to eradicate bacterial pathogens and influence post-sepsis immunosuppression. Parkin, AMPK levels, and the effects of AMPK activators were investigated in human leukocytes from sepsis survivors as well as wild type and Park2−/− murine macrophages. In vivo, the impact of AMPK and Parkin was determined in mice subjected to polymicrobial intra-abdominal sepsis and secondary lung bacterial infections. Mice were treated with metformin during established immunosuppression. We showed that bacteria and mitochondria share mechanisms of autophagic killing/clearance triggered by sentinel events that involve depolarization of mitochondria and recruitment of Parkin in macrophages. Parkin-deficient mice/macrophages fail to form phagolysosomes and kill bacteria. This impairment of host defense is seen in the context of sepsis-induced immunosuppression with decreased levels of Parkin. AMPK activators, including metformin, stimulate Parkin-independent autophagy and bacterial killing in leukocytes from post-shock patients and in lungs of sepsis-immunosuppressed mice. Our results support a dual role of Parkin and AMPK in the clearance of dysfunctional mitochondria and killing of pathogenic bacteria, and explain the immunosuppressive phenotype associated Parkin and AMPK deficiency. AMPK activation appeared to be a crucial therapeutic target for the macrophage immunosuppressive phenotype and to reduce severity of secondary bacterial lung infections and respiratory failure.

Treatment of embolic stroke in rats with bortezomib and recombinant human tissue plasminogen activator

2006 ◽  
Vol 95 (01) ◽  
pp. 166-173 ◽  
Author(s):  
Li Zhang ◽  
Zheng Zhang ◽  
Xianshuang Liu ◽  
Ann Hozeska ◽  
Nancy Stagliano ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Vascular Function ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Therapeutic Window ◽  
Vascular Events ◽  
Tissue Plasminogen

SummaryStroke elicits a progressive vascular dysfunction, which contributes to the evolution of brain injury. Thrombolysis with tissue plasminogen activator (tPA) promotes adverse vascular events that limit the therapeutic window of stroke to three hours. Proteasome inhibitors reduce vascular thrombotic and inflammatory events, and consequently protect vascular function. The present study evaluated the neuroprotective effect of bortezomib,a potent and selective inhibitor of the proteasome, alone and in combination with delayed thrombolytic therapy on a rat model of embolic focal cerebral ischemia. Treatment with bortezomib reduces adverse cerebrovascular events including secondary thrombosis,inflammatory responses,and blood brain barrier (BBB) disruption, and hence reduces infarct volume and neurological functional deficit when administrated within 4 h after stroke onset. Combination of bortezomib and tPA extends the thrombolytic window for stroke to6 h, which is associated with the improvement of vascular patency and integrity. Real time RT-PCR of endothelial cells isolated by laser-capture microdissection from brain tissue and Western blot analysis showed that bortezomib upregulates endothelial nitric oxide synthase (eNOS) expression and blocks NF-κB activation. These results demonstrate that bortezomib promotes eNOS dependent vascular protection, and reduces NF-κB dependent vascular disruption, all of which may contribute to neuroprotection after stroke.

scholarly journals Dual functional β-peptide polymer-modified resin beads for bacterial killing and endotoxin adsorption

BMC Materials ◽  
2019 ◽  
Vol 1 (1) ◽  
Author(s):  
Yuxin Qian ◽  
Yue Shen ◽  
Shuai Deng ◽  
Tingyan Liu ◽  
Fan Qi ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Bacterial Resistance ◽  
Resistant Bacteria ◽  
High Concentration ◽  
Major Step ◽  
Bacterial Killing ◽  
Host Defense Peptides ◽  
Dual Functional ◽  
Resin Beads ◽  
Bacteria Killing

Abstract Background Bacterial infections and endotoxin contaminations are serious problems in the production/manufacture of food, water, drinks, and injections. The development of effective materials to kill bacteria and adsorb endotoxins, particularly those caused by gram-negative bacteria, represents a major step toward improved safety. As synthetic mimic of host defense peptides, β-peptide polymers are not susceptible to bacterial resistance and exhibit potent bacteria-killing abilities upon antibiotic-resistant bacteria. This study investigated the potential of synthetic β-peptide polymer-modified polyacrylate (PA) beads to kill bacteria and remove endotoxin, i.e. lipopolysaccharide (LPS), produced by these bacteria. Results Synthetic β-peptide polymer-modified PA beads displayed strong antimicrobial activity against Escherichia coli and methicillin-resistant Staphylococcus aureus, as well as excellent biocompatibility. In addition, these β-peptide polymer-modified beads removed around 90% of the endotoxins, even at 200 EU/mL of LPS, a very high concentration of LPS. Conclusions β-peptide polymer-modified PA beads are efficient in bacterial killing and endotoxin adsorption. Hence, these modified beads demonstrate the potential application in the production/manufacture of food, water, drinks, and injections.

scholarly journals Protective Features of Autophagy in Pulmonary Infection and Inflammatory Diseases

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 123 ◽  
Author(s):  
Kui Wang ◽  
Yi Chen ◽  
Pengju Zhang ◽  
Ping Lin ◽  
Na Xie ◽  
...  
Keyword(s):  
Pulmonary Infection ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Autophagy Pathway ◽  
Pulmonary Arterial ◽  
Cellular Components ◽  
Cellular Stressors

Autophagy is a highly conserved catabolic process involving autolysosomal degradation of cellular components, including protein aggregates, damaged organelles (such as mitochondria, endoplasmic reticulum, and others), as well as various pathogens. Thus, the autophagy pathway represents a major adaptive response for the maintenance of cellular and tissue homeostasis in response to numerous cellular stressors. A growing body of evidence suggests that autophagy is closely associated with diverse human diseases. Specifically, acute lung injury (ALI) and inflammatory responses caused by bacterial infection or xenobiotic inhalation (e.g., chlorine and cigarette smoke) have been reported to involve a spectrum of alterations in autophagy phenotypes. The role of autophagy in pulmonary infection and inflammatory diseases could be protective or harmful dependent on the conditions. In this review, we describe recent advances regarding the protective features of autophagy in pulmonary diseases, with a focus on ALI, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), tuberculosis, pulmonary arterial hypertension (PAH) and cystic fibrosis.

scholarly journals Dextromethorphan Efficiently Increases Bactericidal Activity, Attenuates Inflammatory Responses, and Prevents Group A Streptococcal Sepsis

2011 ◽  
Vol 55 (3) ◽  
pp. 967-973 ◽  
Author(s):  
Ming-Han Li ◽  
Yueh-Hsia Luo ◽  
Chiou-Feng Lin ◽  
Yu-Tzu Chang ◽  
Shiou-Ling Lu ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Inflammatory Responses ◽  
Group A Streptococcus ◽  
Wide Spectrum ◽  
Serum Levels ◽  
Streptococcal Toxic Shock Syndrome ◽  
Necrosis Factor Alpha ◽  
Bacterial Killing ◽  
Air Pouch ◽  
Group A

ABSTRACTGroup A streptococcus (GAS) is an important human pathogen that causes a wide spectrum of diseases, ranging from mild throat and skin infections to severe invasive diseases such as necrotizing fasciitis and streptococcal toxic shock syndrome. Dextromethorphan (DM), a dextrorotatory morphinan and a widely used antitussive drug, has recently been reported to possess anti-inflammatory properties. In this study, we investigated the potential protective effect of DM in GAS infection using an air pouch infection mouse model. Our results showed that DM treatment increased the survival rate of GAS-infected mice. Bacterial numbers in the air pouch were lower in mice treated with DM than in those infected with GAS alone. The bacterial elimination efficacy was associated with increased cell viability and bactericidal activity of air-pouch-infiltrating cells. Moreover, DM treatment prevented bacterial dissemination in the blood and reduced serum levels of the proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), and IL-1β and the chemokines monocyte chemotactic protein 1 (MCP-1), macrophage inflammatory protein 2 (MIP-2), and RANTES. In addition, GAS-induced mouse liver injury was reduced by DM treatment. Taken together, DM can increase bacterial killing and reduce inflammatory responses to prevent sepsis in GAS infection. The consideration of DM as an adjunct treatment in combination with antibiotics against bacterial infection warrants further study.

scholarly journals Soya protein hydrolysates modify the expression of various pro-inflammatory genes induced by fatty acids in ovine phagocytes

2011 ◽  
Vol 108 (7) ◽  
pp. 1246-1255 ◽  
Author(s):  
Ioannis Politis ◽  
Georgios Theodorou ◽  
Antonios D. Lampidonis ◽  
Roubini Chronopoulou ◽  
Antonella Baldi
Keyword(s):  
Gene Expression ◽  
Fatty Acids ◽  
Fatty Acid ◽  
Plasminogen Activator ◽  
Inflammatory Responses ◽  
Soya Protein ◽  
Protein Hydrolysates ◽  
Intercellular Adhesion Molecule ◽  
Inflammatory Genes

The objective of the present study was to test the hypothesis that fatty acids are the circulating mediators acting in a pro-inflammatory manner towards activated circulating ovine monocyte/macrophages and neutrophils. Furthermore, whether soya protein hydrolysates (SPH) inhibit the fatty acid-induced increase in the production of pro-inflammatory responses by ovine phagocytes was tested in vitro. All the fatty acids tested (myristic, palmitic, palmitoleic, stearic and oleic) increased (P < 0·01; C18>C16>C14) membrane-bound urokinase plasminogen activator (u-PA) and u-PA free binding sites in cell membranes of activated ovine blood monocytes/macrophages, but only the C18 fatty acids (stearic, oleic) were effective towards blood neutrophils. The C18 fatty acids up-regulated (P < 0·05) the gene expression of u-PA, u-PA receptor, intercellular adhesion molecule 1 and inducible NO synthase (in monocytes) but not that of cyclo-oxygenase-2, integrin α X and plasminogen activator inhibitor types 1 and 2 by ovine phagocytes. SPH blocked completely or partially all C18 fatty acid-induced changes in the expression of various pro-inflammatory genes. In conclusion, fatty acids selectively ‘activate’ ovine phagocytes, suggesting that these cells ‘sense’ metabolic signals derived from adipocytes. Soya protein peptides inhibit all changes in gene expression induced by fatty acids in ovine phagocytes in vitro. This constitutes a novel mechanism of action.

scholarly journals Pretreatment With Fluticasone Propionate Increases Antibiotic Efficacy During Treatment of Late-Stage Primary Pneumonic Plague

2021 ◽  
Author(s):  
Samantha D. Crane ◽  
Srijon K. Banerjee ◽  
Roger D. Pechous
Keyword(s):  
Fluticasone Propionate ◽  
Late Stage ◽  
Antimicrobial Agents ◽  
Inflammatory Responses ◽  
Severe Pneumonia ◽  
Neutrophil Infiltration ◽  
Host Responses ◽  
Infection Model ◽  
Pneumonic Plague ◽  
Pulmonary Damage

Severe and late-stage pneumonias are often difficult to treat with antibiotics alone due to overwhelming host inflammatory responses mounted to clear infection. These host responses contribute to pulmonary damage leading to acute lung injury, acute respiratory distress syndrome, and death. In order to effectively treat severe and late-stage pneumonias, use of adjunctive therapies must be considered to reduce pulmonary damage when antimicrobial agents can be administered. Pneumonic plague, a severe pneumonia caused by inhalation of Yersinia pestis , is a fatal disease that causes death within six days without antibiotic intervention. Late-stage pneumonic plague is difficult to treat, as antibiotics must be delivered within 24 hours after onset of symptoms to be effective. Here, we use a murine model of primary pneumonic plague to examine how host inflammatory responses impact antibiotic treatment of late-stage pneumonic plague. We developed a murine infection model demonstrating the poor outcomes associated with delayed delivery of antibiotics. We show that pretreatment of mice with intranasal fluticasone propionate increased efficacy of delayed antibiotic delivery and enhanced murine survival. Mice receiving fluticasone propionate also showed decreased bacterial burden and reduced inflammatory pathology in the lungs. Further, we show that treatment and survival correlated with decreased levels of IL-6 and reduced neutrophil infiltration to the lungs. This work demonstrates how host inflammatory responses complicate treatment of late-stage pneumonic plague, and suggests that targeting of host inflammatory responses may improve treatment of severe, late-stage pneumonia.

scholarly journals Macrophage LC3-associated phagocytosis is an immune defense against Streptococcus pneumoniae that diminishes with host aging

2020 ◽  
Vol 117 (52) ◽  
pp. 33561-33569
Author(s):  
Megumi Inomata ◽  
Shuying Xu ◽  
Pallavi Chandra ◽  
Simin N. Meydani ◽  
Genzou Takemura ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Inflammatory Responses ◽  
The Elderly ◽  
Invasive Disease ◽  
Immune Defense ◽  
Bacterial Killing ◽  
Murine Bone Marrow ◽  
Aged Mice ◽  
Age Related ◽  
Old Mice

Streptococcus pneumoniae is a leading cause of pneumonia and invasive disease, particularly, in the elderly. S. pneumoniae lung infection of aged mice is associated with high bacterial burdens and detrimental inflammatory responses. Macrophages can clear microorganisms and modulate inflammation through two distinct lysosomal trafficking pathways that involve 1A/1B-light chain 3 (LC3)-marked organelles, canonical autophagy, and LC3-associated phagocytosis (LAP). The S. pneumoniae pore-forming toxin pneumolysin (PLY) triggers an autophagic response in nonphagocytic cells, but the role of LAP in macrophage defense against S. pneumoniae or in age-related susceptibility to infection is unexplored. We found that infection of murine bone-marrow-derived macrophages (BMDMs) by PLY-producing S. pneumoniae triggered Atg5- and Atg7-dependent recruitment of LC3 to S. pneumoniae-containing vesicles. The association of LC3 with S. pneumoniae-containing phagosomes required components specific for LAP, such as Rubicon and the NADPH oxidase, but not factors, such as Ulk1, FIP200, or Atg14, required specifically for canonical autophagy. In addition, S. pneumoniae was sequestered within single-membrane compartments indicative of LAP. Importantly, compared to BMDMs from young (2-mo-old) mice, BMDMs from aged (20- to 22-mo-old) mice infected with S. pneumoniae were not only deficient in LAP and bacterial killing, but also produced higher levels of proinflammatory cytokines. Inhibition of LAP enhanced S. pneumoniae survival and cytokine responses in BMDMs from young but not aged mice. Thus, LAP is an important innate immune defense employed by BMDMs to control S. pneumoniae infection and concomitant inflammation, one that diminishes with age and may contribute to age-related susceptibility to this important pathogen.

Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein

2006 ◽  
Vol 290 (3) ◽  
pp. G557-G567 ◽  
Author(s):  
Geraldine Canny ◽  
Elke Cario ◽  
Andreas Lennartsson ◽  
Urban Gullberg ◽  
Ciara Brennan ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Molecular Mechanisms ◽  
Biochemical Characterization ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Systemic Disease ◽  
Intestinal Epithelial ◽  
Bacterial Killing ◽  
Intestinal Epithelia ◽  
And Function

Epithelial cells of many mucosal organs have adapted to coexist with microbes and microbial products. In general, most studies suggest that epithelial cells benefit from interactions with commensal microorganisms present at the lumenal surface. However, potentially injurious molecules found in this microenvironment also have the capacity to elicit local inflammatory responses and even systemic disease. We have recently demonstrated that epithelia cells express the anti-infective molecule bactericidal/permeability-increasing protein (BPI). Here, we extend these findings to examine molecular mechanisms of intestinal epithelial cell (IEC) BPI expression and function. Initial experiments revealed a variance of BPI mRNA and protein expression among various IEC lines. Studies of BPI promoter expression in IECs identified regulatory regions of the BPI promoter and revealed a prominent role for CCAAT/enhancer binding protein and especially Sp1/Sp3 in the basal regulation of BPI. To assess the functional significance of this protein, we generated an IEC line stably transfected with full-length BPI. We demonstrated that, whereas epithelia express markedly less BPI protein than neutrophils, epithelial BPI contributes significantly to bacterial killing and attenuating bacterial-elicted proinflammatory signals. Additional studies in murine tissue ex vivo revealed that BPI is diffusely expressed along the crypt-villous axis and that epithelial BPI levels decrease along the length of the intestine. Taken together, these data confirm the transcriptional regulation of BPI in intestinal epithelia and provide insight into the relevance of BPI as an anti-infective molecule at intestinal surfaces.

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