Surfactant Protein (SP)-A Suppresses Preterm Delivery and Inflammation via TLR2

Toll like receptors (TLRs) are pattern-recognition molecules that initiate the innate immune response to pathogens. Pulmonary surfactant protein (SP)-A is an endogenously produced ligand for TLR2 and TLR4. SP-A has been proposed as a fetally produced signal for the onset of parturition in the mouse. We examined the effect of interactions between SP-A and the pathogenic TLR agonists lipopolysaccharide (LPS), peptidoglycan (PGN) and polyinosinic:cytidylic acid (poly(I:C)) (ligands for TLR4, TLR2 and TLR3, respectively) on the expression of inflammatory mediators and preterm delivery. Three types of mouse macrophages (the cell line RAW 264.7, and fresh amniotic fluid and peritoneal macrophages, including macrophages from TLR4 and TLR2 knockout mice) were treated for up to 7 hours with pathogenic TLR agonists with or without SP-A. SP-A alone had no effect upon inflammatory mediators in mouse macrophages and did not independently induce preterm labor. SP-A significantly suppressed TLR ligand-induced expression of inflammatory mediators (interleukin (IL)-1β, tumor necrosis factor (TNF)-α and the chemokine CCL5) via a TLR2 dependent mechanism. In a mouse inflammation-induced preterm delivery model, intrauterine administration of SP-A significantly inhibited preterm delivery, suppressed the expression of proinflammatory mediators and enhanced the expression of the CXCL1 and anti-inflammatory mediator IL-10. We conclude that SP-A acts via TLR2 to suppress TLR ligand-induced preterm delivery and inflammatory responses.</p

The Airway Microbiome at Birth.

Alterations of pulmonary microbiome have been recognized in multiple respiratory disorders. It is critically important to ascertain if an airway microbiome exists at birth and if so, whether it is associated with subsequent lung disease. We found an established diverse and similar airway microbiome at birth in both preterm and term infants, which was more diverse and different from that of older preterm infants with established chronic lung disease (bronchopulmonary dysplasia). Consistent temporal dysbiotic changes in the airway microbiome were seen from birth to the development of bronchopulmonary dysplasia in extremely preterm infants. Genus Lactobacillus was decreased at birth in infants with chorioamnionitis and in preterm infants who subsequently went on to develop lung disease. Our results, taken together with previous literature indicating a placental and amniotic fluid microbiome, suggest fetal acquisition of an airway microbiome. We speculate that the early airway microbiome may prime the developing pulmonary immune system, and dysbiosis in its development may set the stage for subsequent lung disease

Platelet-Activating Factor Induces TLR4 Expression in Intestinal Epithelial Cells: Implication for the Pathogenesis of Necrotizing Enterocolitis

Necrotizing enterocolitis (NEC) is a leading cause of morbidity and mortality in neonatal intensive care units, however its pathogenesis is not completely understood. We have previously shown that platelet activating factor (PAF), bacteria and TLR4 are all important factors in the development of NEC. Given that Toll-like receptors (TLRs) are expressed at low levels in enterocytes of the mature gastrointestinal tract, but were shown to be aberrantly over-expressed in enterocytes in experimental NEC, we examined the regulation of TLR4 expression and signaling by PAF in intestinal epithelial cells using human and mouse in vitro cell lines, and the ex vivo rat intestinal loop model. In intestinal epithelial cell (IEC) lines, PAF stimulation yielded upregulation of both TLR4 mRNA and protein expression and led to increased IL-8 secretion following stimulation with LPS (in an otherwise LPS minimally responsive cell line). PAF stimulation resulted in increased human TLR4 promoter activation in a dose dependent manner. Western blotting and immunohistochemical analysis showed PAF induced STAT3 phosphorylation and nuclear translocation in IEC, and PAF-induced TLR4 expression was inhibited by STAT3 and NFκB Inhibitors. Our findings provide evidence for a mechanism by which PAF augments inflammation in the intestinal epithelium through abnormal TLR4 upregulation, thereby contributing to the intestinal injury of NEC

Inflammatory signals that regulate intestinal epithelial renewal, differentiation, migration and cell death: Implications for necrotizing enterocolitis

Policijski službenici u obavljanju svojih službenih poslova i zadaća, dužni su postupati u skladu sa zakonom i drugim propisima, a kada ne postupaju u skladu sa zakonom i ne obavljaju dužnosti koje su im propisane zakonom dolazi do povrede službene dužnosti. Za povrede službene dužnosti protiv policijskih službenika u Odjelima prvostupanjskog disciplinskog sudovanja u Zagrebu, Splitu, Rijeci i Osijeku, sa obzirom na mjesnu nadležnost, provode se disciplinski postupci, a također unutar Ministarstva unutarnjih poslova ustrojen je i Drugostupanjski disciplinski sud u Zagrebu nadležan za područje cijele Republike Hrvatske. S obzirom da policijski službenici u obavljanju svojih poslova predstavljaju i policiju kao službu za najteže povrede službene dužnosti dok se utvrđuje disciplinska, kaznena odnosno prekršajna odgovornost policijskog službenika opravdano je da isti za vrijeme postupka bude udaljen iz službe.Police officers in the performance of their official duties and tasks are obliged to act in accordance with the law and other regulations, and when they do not act in accordance with the law and do not perform the duties prescribed by law, there is a violation of official duty. For disciplinary action against police officers in the Departments of First Instance Disciplinary Jurisdiction in Zagreb, Split, Rijeka and Osijek, with respect to local jurisdiction, disciplinary proceedings are carried out, and a Secondary Disciplinary Court in Zagreb with jurisdiction over the entire territory is established within the Ministry of the Interior. Of the Republic of Croatia. Considering that police officers represent the police in the performance of their duties, as the service for the most serious violations of official duty, while determining the disciplinary, criminal or misdemeanor responsibility of a police officer, it is justified that he or she be removed from service during the proceedings

TGFβ-dependent induction of interleukin-11 and interleukin-8 involves SMAD and p38 MAPK pathways in breast tumor models with varied bone metastases potential

We have delineated TGFβ signaling pathways in the production of osteolytic factors interleukin-8 and interleukin-11 in breast cancer cells with different bone metastases potential. Bone seeking MDA-MB-231(hm) cells expressed higher levels of IL-11, but lower levels of IL-8 compared to MDA-MB-231 cells. MCF-7 cells (mainly osteoblastic) did not express IL-8 or IL-11; MDA-MB-468 cells (weakly metastatic) expressed IL-8, but not IL-11. The upregulation of IL-11 and IL-8 was associated with the rapid activation of SMAD2/3 and p38 MAPK through the TGFβ/TGFβR system. Analysis of TGFβ receptors indicated that MCF-7 cells do not express TGFβRII, and MDA-MB-468 cells do not express SMAD4. Inactivation of SMAD4 or p38PMAPK gene via RNAi resulted in the inhibition of IL-11 and IL-8 production in MDA-MB-231(hm) cells; and overexpression of SMAD4 gene resulted in IL-11 production in MDA-MB-468 cells. TGFβ-1 induced SMAD3 translocation to the nuclei in MDA-MB-231, MDA-MB-231(hm) as well as in SMAD4 deficient MDA-MB-468, indicating that an alternate non-canonical pathway could be responsible for TGFβ-1 induced cytokine production in MDA-MB-468 cells. Thus, four breast cancer cell lines used in this study show differential expression and upregulation of the osteolytic factors in response to TGFβ-1 that involves both SMAD pathway, a non-canonical SMAD pathway, as well as p38 MAPK pathways

Surfactant Protein (SP)-A Suppresses Preterm Delivery and Inflammation via TLR2

<div><p>Toll like receptors (TLRs) are pattern-recognition molecules that initiate the innate immune response to pathogens. Pulmonary surfactant protein (SP)-A is an endogenously produced ligand for TLR2 and TLR4. SP-A has been proposed as a fetally produced signal for the onset of parturition in the mouse. We examined the effect of interactions between SP-A and the pathogenic TLR agonists lipopolysaccharide (LPS), peptidoglycan (PGN) and polyinosinic:cytidylic acid (poly(I:C)) (ligands for TLR4, TLR2 and TLR3, respectively) on the expression of inflammatory mediators and preterm delivery. Three types of mouse macrophages (the cell line RAW 264.7, and fresh amniotic fluid and peritoneal macrophages, including macrophages from TLR4 and TLR2 knockout mice) were treated for up to 7 hours with pathogenic TLR agonists with or without SP-A. SP-A alone had no effect upon inflammatory mediators in mouse macrophages and did not independently induce preterm labor. SP-A significantly suppressed TLR ligand-induced expression of inflammatory mediators (interleukin (IL)-1β, tumor necrosis factor (TNF)-α and the chemokine CCL5) via a TLR2 dependent mechanism. In a mouse inflammation-induced preterm delivery model, intrauterine administration of SP-A significantly inhibited preterm delivery, suppressed the expression of proinflammatory mediators and enhanced the expression of the CXCL1 and anti-inflammatory mediator IL-10. We conclude that SP-A acts via TLR2 to suppress TLR ligand-induced preterm delivery and inflammatory responses.</p></div