Transmission plays an important role in establishing pneumococcal colonization. It comprises three key events: shedding to transmit, entering into a susceptible new host, and adhering to the mucosal surface. Shedding of pneumococci from the respiratory tract of a colonized host is a pivotal step in transmission. Using a co-housed littermate mouse model, we evaluated the importance of the susceptibility to colonization of Streptococcus pneumoniae TIGR4 strain shed from index pups to non-colonized naïve contact pups. Despite sufficient pneumococcal shedding from the colonized host, S. pneumoniae was not contagious between littermates. Neutrophils infiltrated the nasal mucosa of contact pups and contributed to susceptibility of pneumococcal colonization during the course of transmission. Rejection of pneumococcal colonization in the contact pups was associated with accumulation of neutrophils in the nasal mucosa. Inflammation, characterized by neutrophil infiltration, prevents newly entering pneumococci from adhering to the respiratory epithelium in contact mice, suggesting that it plays an important role in reducing the rate of transmission in the initial response of naïve susceptible hosts to pneumococcal acquisition. The initial response of contact mice may regulate neutrophil and/or macrophage infiltration and control the acquisition of existing pneumococci.
- MeSH
- infiltrace neutrofily MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- novorozená zvířata MeSH
- pneumokokové infekce * MeSH
- Streptococcus pneumoniae * MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Myocardial recovery from ischemia-reperfusion (IR) is shaped by the interaction of many signaling pathways and tissue repair processes, including the innate immune response. We and others previously showed that sustained expression of the transcriptional co-activator yes-associated protein (YAP) improves survival and myocardial outcome after myocardial infarction. Here, we asked whether transient YAP expression would improve myocardial outcome after IR injury. After IR, we transiently activated YAP in the myocardium with modified mRNA encoding a constitutively active form of YAP (aYAP modRNA). Histological studies 2 d after IR showed that aYAP modRNA reduced cardiomyocyte (CM) necrosis and neutrophil infiltration. 4 wk after IR, aYAP modRNA-treated mice had better heart function as well as reduced scar size and hypertrophic remodeling. In cultured neonatal and adult CMs, YAP attenuated H2O2- or LPS-induced CM necrosis. TLR signaling pathway components important for innate immune responses were suppressed by YAP/TEAD1. In summary, our findings demonstrate that aYAP modRNA treatment reduces CM necrosis, cardiac inflammation, and hypertrophic remodeling after IR stress.
- MeSH
- adaptorové proteiny signální transdukční aplikace a dávkování genetika MeSH
- apoptóza účinky léků MeSH
- editace RNA MeSH
- infiltrace neutrofily účinky léků MeSH
- injekce intramuskulární MeSH
- kardiomegalie farmakoterapie etiologie MeSH
- kardiomyocyty metabolismus MeSH
- kultivované buňky MeSH
- lidé MeSH
- messenger RNA aplikace a dávkování genetika MeSH
- modely nemocí na zvířatech MeSH
- myokard imunologie MeSH
- myokarditida farmakoterapie etiologie MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- novorozená zvířata MeSH
- reperfuzní poškození myokardu komplikace MeSH
- transkripční faktory aplikace a dávkování genetika MeSH
- viabilita buněk účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Eye rheum is a physiological discharge, which accumulates at the medial angle of the healthy eye soon after opening in the morning. Microscopic evaluation of eye rheum revealed the presence of viable neutrophils, bacteria, epithelial cells, and particles, aggregated by neutrophil extracellular traps. We observed that in the evening, during eye closure, high C5a recruited neutrophils to the tear film and activated them. In this hypoxic area rich in CO2 , neutrophils fight microbial aggressors by degranulation. Immediately after eye opening, the microenvironment of the ocular surface changes, the milieu gets normoxic, and loss of CO2 induces subtle alkalinization of tear film. These conditions favored the formation of neutrophil extracellular traps (NETs) that initially covers the ocular surface and tend to aggregate by eyelid blinking. These aggregated neutrophil extracellular traps (aggNETs) are known as eye rheum and contain several viable neutrophils, epithelial cells, dust particles, and crystals packed together by NETs. Similar to aggNETs induced by monosodium urate crystals, the eye rheum shows a robust proteolytic activity that degraded inflammatory mediators before clinically overt inflammation occur. Finally, the eye rheum passively floats with the tear flow to the medial angle of the eye for disposal. We conclude that the aggNETs-based eye rheum promotes cleaning of the ocular surface and ameliorates the inflammation on the neutrophil-rich ocular surfaces.
The fused quinazolinone derivative, RX-207, is chemically and functionally related to small molecule inhibitors of protein binding to glycosaminoglycans (SMIGs). Composed of a planar aromatic amine scaffold, it inhibits protein binding to glycosaminoglycans (GAGs). RX-207 reduced neutrophil migration in thioglycollate-induced peritonitis (37%), inhibited carrageenan-induced paw edema (32%) and cerulein-induced pancreatitis (28%), and increased animal survival in the mouse model of cecal ligation and puncture (CLP)-induced sepsis (60%). The mechanism of RX-207 action, analyzed by UV spectroscopy, confirmed that which was elucidated for chemically related anti-inflammatory SMIGs. RX-207 binding to cell surface GAGs can account for the inhibition of neutrophil recruitment via the micro-vasculature and as a consequence, the reduction of neutrophil mediated tissue damage in the animal models of inflammation and improved survival of mice in CLP-induced sepsis.
- MeSH
- antiflogistika farmakologie MeSH
- buněčná adheze účinky léků MeSH
- cékum mikrobiologie chirurgie MeSH
- chinazolinony farmakologie MeSH
- edém chemicky indukované metabolismus patologie prevence a kontrola MeSH
- glykosaminoglykany metabolismus MeSH
- infiltrace neutrofily účinky léků MeSH
- ligace MeSH
- modely nemocí na zvířatech MeSH
- myši inbrední BALB C MeSH
- neutrofily účinky léků metabolismus mikrobiologie MeSH
- pankreatitida chemicky indukované metabolismus patologie prevence a kontrola MeSH
- peritonitida chemicky indukované metabolismus patologie prevence a kontrola MeSH
- punkce MeSH
- sepse metabolismus mikrobiologie patologie prevence a kontrola MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: Using killed microorganisms or their parts to stimulate immunity for cancer treatment dates back to the end of 19(th) century. Since then, it undergone considerable development. Our novel approach binds ligands to the tumor cell surface, which stimulates tumor phagocytosis. The therapeutic effect is further amplified by simultaneous application of agonists of Toll-like receptors. We searched for ligands that induce both a strong therapeutic effect and are safe for humans. METHODS: B16-F10 murine melanoma model was used. For the stimulation of phagocytosis, mannan or N-formyl-methionyl-leucyl-phenylalanine, was covalently bound to tumor cells or attached using hydrophobic anchor. The following agonists of Toll-like receptors were studied: monophosphoryl lipid A (MPLA), imiquimod (R-837), resiquimod (R-848), poly(I:C), and heat killed Listeria monocytogenes. RESULTS: R-848 proved to be the most suitable Toll-like receptor agonist for our novel immunotherapeutic approach. In combination with covalently bound mannan, R-848 significantly reduced tumor growth. Adding poly(I:C) and L. monocytogenes resulted in complete recovery in 83% of mice and in their protection from the re-transplantation of melanoma cells. CONCLUSION: An efficient cancer treatment results from the combination of Toll-like receptor agonists and phagocytosis stimulating ligands bound to the tumor cells.
- MeSH
- cytokiny metabolismus MeSH
- fagocytóza MeSH
- imidazoly farmakologie MeSH
- imunoterapie * metody MeSH
- infiltrace neutrofily imunologie MeSH
- ligandy MeSH
- mannany imunologie MeSH
- melanom experimentální MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- nádory imunologie metabolismus patologie terapie MeSH
- neutrofily imunologie metabolismus MeSH
- poly I-C imunologie MeSH
- přirozená imunita * MeSH
- respirační vzplanutí imunologie MeSH
- toll-like receptory agonisté metabolismus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Matrix metalloproteinases (MMPs) are potential biomarkers for disease activity in inflammatory bowel disease (IBD). However, clinical trials targeting MMPs have not succeeded, likely due to poor understanding of the biological functions of individual MMPs. Here, we explore the role of MMP-19 in IBD pathology. Using a DSS-induced model of colitis, we show evidence for increased susceptibility of Mmp-19-deficient (Mmp-19(-/-)) mice to colitis. Absence of MMP-19 leads to significant disease progression, with reduced survival rates, severe tissue destruction, and elevated levels of pro-inflammatory modulators in the colon and plasma, and failure to resolve inflammation. There was a striking delay in neutrophil infiltration into the colon of Mmp-19(-/-) mice during the acute colitis, leading to persistent inflammation and poor recovery; this was rescued by reconstitution of irradiated Mmp-19(-/-) mice with wild-type bone marrow. Additionally, Mmp-19-deficient macrophages exhibited decreased migration in vivo and in vitro and the mucosal barrier appeared compromised. Finally, chemokine fractalkine (CX3CL1) was identified as a novel substrate of MMP-19, suggesting a link between insufficient processing of CX3CL1 and cell recruitment in the Mmp-19(-/-) mice. MMP-19 proves to be a critical factor in balanced host response to colonic pathogens, and for orchestrating appropriate innate immune response in colitis.
- MeSH
- chemokin CX3CL1 metabolismus MeSH
- cytokiny metabolismus MeSH
- idiopatické střevní záněty imunologie MeSH
- infiltrace neutrofily genetika MeSH
- kolitida chemicky indukované imunologie MeSH
- kolon imunologie MeSH
- kultivované buňky MeSH
- lidé MeSH
- makrofágy imunologie MeSH
- mediátory zánětu metabolismus MeSH
- metaloproteinasy secernované do matrix genetika metabolismus MeSH
- myši inbrední C57BL MeSH
- myši knockoutované MeSH
- myši MeSH
- pohyb buněk MeSH
- přirozená imunita MeSH
- progrese nemoci MeSH
- síran dextranu MeSH
- střevní sliznice imunologie patologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The relationship between obesity and renal lesions, especially in low estrogen levels, has been less documented. The aim of this study was to assess the renal changes in diet-induced obesity in ovariectomized rats. Wistar rats were ovariectomized or sham-operated and divided into four groups: sham-operated rats fed a standard diet (SSD); ovariectomized rats fed a standard diet (OSD); sham-operated rats fed a high-fat diet (SHFD); ovariectomized rats fed a high-fat diet (OHFD). Body weight and blood pressure were measured weekly. The rats were killed 24 weeks after initiation of standard or high-fat diet treatment, the kidneys were removed for immunohistochemical and histological studies. Blood and urine samples were collected to quantify sodium, potassium and creatinine. OHFD rats presented increases in visceral adipose tissue, serum insulin levels, blood pressure and proteinuria, and a decrease in fractional excretion of sodium as well. Histological and morphometric studies showed focal alterations in the renal cortex. Expression of macrophages, lymphocytes, nuclear factor-kappa B (NF-kappaB), Proliferating Cell Nuclear Antigen (PCNA), angiotensin II (ANG II) and vimentin was greater in OHFD rats than in control rats. Thus, these results demonstrate that the high-fat diet in ovariectomized rats promoted renal function and structure changes, renal interstitial infiltration of mononuclear cells and increased expression of ANG II and NF-kappaB.
- MeSH
- angiotensin II biosyntéza MeSH
- dieta s vysokým obsahem tuků škodlivé účinky MeSH
- energetický příjem MeSH
- infiltrace neutrofily MeSH
- inzulin krev MeSH
- krevní tlak fyziologie MeSH
- krysa rodu rattus MeSH
- ledviny patologie MeSH
- makrofágy MeSH
- NF-kappa B biosyntéza MeSH
- obezita patologie MeSH
- ovarektomie * MeSH
- potkani Wistar MeSH
- tělesná hmotnost MeSH
- TNF-alfa krev MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Bronchopulmonální onemocnění cystické fibrózy (CF) je spojeno s neutrofilním zánětem. Leukotrien (LT) B4 je důležitým chemotaktickým faktorem neutrofilních leukocytů (NF). Podání n-3 polynenasycených mastných kyselin (PUFA) vede k syntéze biologicky méně aktivního LTB5. Cílem práce bylo porovnat zánětlivé parametry (pH a LTB4) kondenzátu vydechovaného vzduchu (KVV) u stabilní CF a zdravých kontrol, zhodnotit jejich vztah k plicním funkcím, stavu výživy a systémovým zánětlivým parametrům a dále zhodnotit vliv suplementace n-3 PUFA. 12 nemocných se stabilní CF (5 mužů) v průměrném věku 25,6 roku mělo ve srovnání se zdravými dobrovolníky (n=12; 4 muži; průměrný věk 27,3 roku) vyšší koncentraci LTB4 v KVV (174,6 vs. 82,6 pg/ml; p=0,011) a nesignifikantně nižší pH KVV (5,95 vs. 6,13). U nemocných s CF korelovala koncentrace LTB4 v KVV s koncentrací C-reaktivního proteinu v séru (r=0,629; p=0,028) a hodnota pH v KVV s hodnotou body mass indexu (r=0,639; p=0,025) a počtem neutrofilních granulocytů v krvi (r=-0,686; p=0,014). Po šesti týdnech suplementace n-3 PUFA v dávce odpovídající 1,3 % kalorického příjmu došlo u nemocných s CF (n=9) k vzestupu hodnoty pH KVV (6,08 vs. 6,32; p=0,042) a nesignifikantnímu poklesu koncentrace LTB4 v KVV (173,0 vs. 120,5 pg/ml). Uzavíráme, že nemocní s CF měli více vyjádřené zánětlivé parametry v KVV oproti zdravým kontrolám. Zánětlivé parametry v KVV korelovaly se systémovými zánětlivými markery. Suplementace n-3 PUFA má tendenci snižovat koncentraci LTB4 v KVV a signifikantně snižuje pH KVV, což může odrážet zmírnění neutrofilního zánětu dýchacích cest u nemocných s CF.
Bronchopulmonary disease in cystic fibrosis (CF) is coupled with neutrophilic inflammation. Leukotriene (LT) B4 is an important chemoattractant for neutrophilic leukocytes. Supplementation with n-3 polyunsaturated fatty acids (PUFA) leads to synthesis of biologically less active LTB5. The aim of this study was to compare inflammatory markers (pH and LTB4) in exhaled breath condensate (EBC) in stable CF and healthy controls, to evaluate their relation to lung function, nutritional status and systemic inflammatory markers, and also to assess the effect of supplementation with n-3 PUFA. Twelve stable CF patients (5 males) with a mean age of 25.6 years had higher concentrations of EBC LTB4 (174.6 vs. 82.6 pg/ml; p = 0.011) and insignificantly lower values of EBC pH (5.95 VS. 6.13) when compared with healthy controls (n = 12; 4 males; mean age 27.3 years). In CF patients, EBC LTB4 concentration correlated with serum C-reactive protein concentration (r = 0.629; p = 0.028) and EBC pH value correlated with the body mass index (r = 0.639; p = 0.025) and blood neutrophil granulocytes count (r = -0.686; p = 0.014). After six weeks of n-3 PUFA supplementation (doses corresponding to 1.3 % of calorie intake), nine CF patients had higher EBC pH values (6.08 vs. 6.32; p = 0.042) and insignificantly lower EBC LTB4 concentration (173.0 vs. 120.5 pg/ml). We conclude that CF patients have more pronounced inflammatory parameters in EBC when compared with healthy controls. EBC inflammatory parameters correlated with systemic inflammatory markers. After n-3 PUFA treatment, EBC LTB4 concentration tended to be lower and EBC was significantly less acid, which may reflect less intense neutrophilic inflammation.
