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Transfusion‑related acute lung injury (TRALI) is a serious complication characterized by the acute onset of non‑cardiogenic pulmonary edema following transfusion of blood products. It is not known whether rapamycin has an effect on TRALI that is caused by blood transfusion. The aim of the present study was to determine the effect of rapamycin on early stage apoptosis of neutrophils in Sprague‑Dawley rats with acute lung injury. Animal models of TRALI and acute pancreatitis‑associated lung injury (APALI) were prepared using Sprague-Dawley rats and histopathological examination of lung tissues was used to validate acute lung injury models. Peripheral blood neutrophils were isolated and early stage apoptosis of neutrophils was detected by flow cytometry. The animal models of TRALI and APALI were constructed successfully. Early stage apoptosis of neutrophils increased in the TRALI group and decreased in the APALI group (P<0.05), while the apoptosis rates in rapamycin intervention TRALI and APALI groups were not significantly different compared to the rate in the control group (P>0.05). In conclusion, early stage apoptosis of neutrophils in TRALI was different from that in APALI, and rapamycin had a limited protective effect on TRALI and APALI in Sprague‑Dawley rats. [ABSTRACT FROM AUTHOR]

Study Question: Do human trophoblast cells modulate neutrophil extracellular trap (NET) formation, reactive oxygen species (ROS) synthesis and neutrophil apoptosis through mechanisms involving vasoactive intestinal peptide (VIP)?Summary Answer: Trophoblast cells inhibited NET formation and ROS synthesis and enhanced neutrophil apoptosis through VIP-mediated pathways in a model of maternal-placental interaction.What Is Known Already: Immune homeostasis maintenance at the maternal-placental interface is mostly coordinated by trophoblast cells. Neutrophil activation and NET formation increases in pregnancies complicated by exacerbated pro-inflammatory responses. VIP has anti-inflammatory and immunosuppressant effects and is synthesized by trophoblast cells.Study Design, Size, Duration: This is a laboratory-based observational study that sampled circulating neutrophils from 50 healthy volunteers to explore their response in vitro to factors derived from human trophoblast cells.Participants/materials, Setting, Methods: Peripheral blood neutrophils were isolated from healthy volunteers and tested in vitro with first trimester trophoblast cell line (Swan-71 and HTR8) conditioned media (CM) or with VIP. The effect of VIP and trophoblast CM on NET formation was assessed by co-localization of elastase and DNA by confocal microscopy, DNA release and elastase activity measurement. Neutrophil apoptosis was determined by flow cytometry or fluorescence microscopy. ROS formation was assessed by flow cytometry with a fluorescent probe. VIP silencing was performed by siRNA transfection. For phagocytosis of apoptotic neutrophils, autologous monocytes were sampled, and engulfment and cytokines were assessed by flow cytometry and ELISA.Main Results and the Role Of Chance: Trophoblast CM and 10 nM VIP promoted neutrophil deactivation by preventing phorbol myristate acetate-induced NET formation and ROS synthesis while they increased neutrophil spontaneous apoptosis and reversed the anti-apoptotic effect of lipopolysaccharide (all P < 0.05 versus control). The effects of trophoblast CM were prevented by a VIP antagonist or when VIP knocked-down trophoblast cells were used (P < 0.05 versus control). Neutrophils driven to apoptosis by trophoblast CM could be rapidly engulfed by monocytes without increasing IL-12 production.Large Scale Data: Not applicable.Limitations, Reasons For Caution: The mechanisms of neutrophil deactivation by trophoblast VIP are based on the results obtained with neutrophils drawn from peripheral blood of healthy individuals interacting with trophoblast cell lines in vitro. These studies were designed to investigate biological processes at the cellular and molecular level; therefore, they have the limitations of studies in vitro and it is not possible to ascertain if these mechanisms operate similarly in vivo. We tested 50 neutrophil samples from healthy volunteers that have a normal variability in their responses. Cell lines derived from human trophoblast were used, and we cannot rule out a differential behavior of trophoblast cells in contact with neutrophils in vivo.Wider Implications Of the Findings: Results presented here are consistent with an active mechanism through which neutrophils in contact with trophoblast cells would be deactivated and silently cleared by decidual macrophages throughout pregnancy. They support a novel immunomodulatory role of trophoblast VIP on neutrophils at the placenta, providing new clues for pharmacological targeting of immune and trophoblast cells in pregnancy complications associated with exacerbated inflammation.Study Funding/competing Interests: This work was funded by the National Agency of Sciences and Technology (PICT 2011-0144, 2014-0657 and 2013-2177) and University of Buenos Aires (UBACyT 20020130100040BA, 20020150100161BA and 20020130100744BA). The authors declare no competing interests. [ABSTRACT FROM AUTHOR]

Inflammation resolution is an active process that involves cellular events such as apoptosis and efferocytosis, which are key steps in the restoration of tissue homeostasis. Hepatocyte growth factor (HGF) is a growth factor mostly produced by mesenchymal-origin cells and has been described to act via MET receptor tyrosine kinase. The HGF/MET axis is essential for determining the progression and severity of inflammatory and immune-mediated disorders. Here, we investigated the effect of blocking the HGF/MET signalling pathway by PF-04217903 on the resolution of established models of neutrophilic inflammation. In a self-resolving model of gout induced by MSU crystals, HGF expression on periarticular tissue peaked at 12 h, the same time point that neutrophils reach their maximal accumulation in the joints. The HGF/MET axis was activated in this model, as demonstrated by increased levels of MET phosphorylation in neutrophils (Ly6G+ cells). In addition, the number of neutrophils was reduced in the knee exudate after PF-04217903 treatment, an effect accompanied by increased neutrophil apoptosis and efferocytosis and enhanced expression of Annexin A1, a key molecule for inflammation resolution. Reduced MPO activity, IL-1β and CXCL1 levels were also observed in periarticular tissue. Importantly, PF-04217903 reduced the histopathological score and hypernociceptive response. Similar findings were obtained in LPS-induced neutrophilic pleurisy. In human neutrophils, the combined use of LPS and HGF increased MET phosphorylation and provided a prosurvival signal, whereas blocking MET with PF-04217903 induced caspase-dependent neutrophil apoptosis. Taken together, these data demonstrate that blocking HGF/MET signalling may be a potential therapeutic strategy for inducing the resolution of neutrophilic inflammatory responses. [Display omitted] [ABSTRACT FROM AUTHOR]

Acute lung injury (ALI) is one of the fatal complications of respiratory virus infections such as influenza virus and coronavirus, which has high clinical morbidity and mortality. Jinhua Qinggan granules (JHQG) has been approved by China Food and Drug Administration in the treatment of H1N1 influenza and mild or moderate novel coronavirus disease 2019 (COVID-19), which is an herbal formula developed based on Maxingshigan decoction and Yinqiao powder that have been used to respiratory diseases in China for thousands of years. However, the underlying mechanism of JHQG in treating infectious diseases remains unclear. This study investigated the effects of JHQG on neutrophil apoptosis and key signaling pathways in lipopolysaccharide (LPS) -induced ALI mice in order to explore its mechanism of anti-inflammation. The effect of JHQG on survival rate was observed in septic mouse model by intraperitoneal injection of LPS (20 mg/kg). To better pharmacological evaluation, the mice received an intratracheal injection of 5 mg/kg LPS. Lung histopathological changes, wet-to-dry ratio of the lungs, and MPO activity in the lungs and total protein concentration, total cells number, TNF-α, IL-1β, IL-6, and MIP-2 levels in BALF were assessed. Neutrophil apoptosis rate was detected by Ly6G-APC/Annexin V-FITC staining. Key proteins associated with apoptosis including caspase 3/7 activity, Bcl-xL and Mcl-1 were measured by flow cytometry and confocal microscope, respectively. TLR4 receptor and its downstream signaling were analyzed by Western blot assay and immunofluorescence, respectively. JHQG treatment at either 6 or 12 g/kg/day resulted in 20% increase of survival in 20 mg/kg LPS-induced mice. In the model of 5 mg/kg LPS-induced mice, JHQG obviously decreased the total protein concentration in BALF, wet-to-dry ratio of the lungs, and lung histological damage. It also attenuated the MPO activity and the proportion of Ly6G staining positive neutrophils in the lungs, as well as the MIP-2 levels in BALF were reduced. JHQG inhibited the expression of Mcl-1 and Bcl-xL and enhanced caspase-3/7 activity, indicating that JHQG partially acted in promoting neutrophil apoptosis via intrinsic mitochondrial apoptotic pathway. The levels of TNF-α, IL-1β, and IL-6 were significantly declined in LPS-induced mice treated with JHQG. Furthermore, JHQG reduced the protein expression of TLR4, MyD88, p-p65 and the proportion of nuclei p65, suggesting that JHQG treatment inhibited TLR4/MyD88/NF-κB pathway. JHQG reduced pulmonary inflammation and protected mice from LPS-induced ALI by promoting neutrophil apoptosis and inhibition of TLR4/MyD88/NF-κB pathway, suggesting that JHQG may be a promising drug for treatment of ALI. [Display omitted] • Jinhua Qinggan granules promotes neutrophil apoptosis via intrinsic apoptotic pathway. • Jinhua Qinggan granules inhibits TLR4/MyD88/NF-κB signaling pathway. • Jinhua Qinggan granules alleviates lipopolysaccharide-induced pulmonary inflammation. [ABSTRACT FROM AUTHOR]

The object of the study was to determine if apoptosis of neutrophils and their subsequent elimination from the mammary gland by macrophages are modulated by an infection of Streptococcus uberis. The experiments were carried out in 5 clinically normal Holstein × Bohemian Red Pied crossbred heifers, aged 14 to 18 months. Before the experimental infection mammary glands were stimulated by PBS as a control. The samples of cell populations were obtained by lavages of the mammary glands in 4 intervals (24, 48, 72 and 168 h) after the PBS and after the experimental infection. Flow cytometry was used to determine the Annexin V positive and propidium jodide negative neutrophils (Annexin V+/PI-). The light microscopy was used to determine apoptotic neutrophils and myeloperoxidase (MPO) positive macrophages. After PBS and S. uberis administration the total number of both Annexin V+/PI- neutrophils and karyopycnotic neutrophils peaked at 24 hours. The highest percentages of Annexin V+/PI- neutrophils were detected at 72 h after PBS and S. uberis, respectively. The highest percentages of karyopycnotic neutrophils were detected at 72 h after PBS and 168 h after S. uberis, respectively. The total number of MPO+ macrophages was the highest at 24 h after PBS and 72 h after S. uberis. The percentage of MPO+ macrophages was the highest at 72 h after PBS and S. uberis. The results of this study demonstrate that during experimental infection of the mammary gland by S. uberis, the apoptosis of neutrophils is modulated. Apoptosis of neutrophils and the subsequent phagocytosis of apoptotic neutrophils by macrophages were delayed. This may cause the transition of the acute inflammatory reaction to a chronic state.

Dysregulation of neutrophil apoptosis causes pathogenesis and aggravation of allergy. S100A9 exists as one of the proteins in the neutrophils, triggering inflammatory responses by activating the immune cells. In this study, we investigated whether S100A9 affects constitutive neutrophil apoptosis by activating the monocytes in normal and allergic subjects. Supernatant from human monocytic THP-1 cells after treatment with S100A9 suppressed normal neutrophil apoptosis by inhibiting the activations of caspase 9 and caspase 3. S100A9 upregulated the release of MCP-1, IL-6, and IL-8 in THP-1 cells. An increase in cytokine was suppressed by CLI-095, a Toll-like receptor (TLR) 4 inhibitor, PP2, a Src inhibitor, rottlerin, a PKCδ inhibitor, MAP kinase inhibitors, including PD98059, SB202190, and SP600125, and BAY-11-7085, an NF-κB inhibitor. Src, PKCδ, ERK1/2, p38 MAPK, and JNK were phosphorylated by S100A9. The phosphorylation of Src and PKCδ was suppressed by CLI-095, and the activation of ERK1/2, p38 MAPK, and JNK was inhibited by CLI-095, PP2, and rottlerin. S100A9 induced NF-κB activity, and the activation was suppressed by CLI-095, PP2, rottlerin, and MAPK kinase inhibitors. In normal and allergic subjects, supernatant from normal and allergic monocytes after stimulation with S100A9 suppressed normal and allergic neutrophil apoptosis, respectively; MCP-1, IL-6, and IL-8 in the supernatant was increased by S100A9. The cytokine secretion induced by S100A9 is related to TLR4, Src, PKCδ, ERK1/2, p38 MAPK, JNK, and NF-κB. Taken together, S100A9 induces anti-apoptotic effect on normal and allergic neutrophils by increasing cytokine secretion of monocytes. These findings may help us to better understand neutrophil apoptosis regulated by S100A9 and pathogenesis of allergic diseases. [ABSTRACT FROM AUTHOR]

Galactosaminogalactan (GAG) is an extracellular polysaccharide produced by the mycelium of the opportunistic human fungal pathogen Aspergillus fumigatus. GAG is the first polysaccharide described as a virulence factor in medical mycology. This review presents our current knowledge of the structural organization and biosynthesis of this polymer. The function of this molecule as an adhesin that also masks Aspergillus PAMPs and the impact of GAG on the modulation of the host immune response by inducing neutropenia and blocking the IL-1 signaling pathway also will be emphasised. [ABSTRACT FROM AUTHOR]

Upon entry to the systemic circulation, neutrophils exhibit a short mean time to cell death. The viability of most cell types in a steady state is preserved by the interplay of the Bcl-2 family of proteins, wherein the anti-apoptotic members inhibit the action of their pro-apoptotic counterparts. Neutrophils, however, display absent or severely reduced expression of several anti-apoptotic Bcl-2 family proteins. Hence, they rely on the expression of Mcl-1, an anti-apoptotic member of the Bcl-2 family, for survival. This protein is uniquely short-lived relative to related proteins and its loss likely precipitates the induction of apoptosis in neutrophils. This review describes the role of Mcl-1 in the neutrophil in the context of apoptosis and highlights the proteins' importance to the cell. We also address neutrophil apoptosis in the broader context of the cells' response to pathogens, focussing particularly on the strategies used by pathogens to manipulate the apoptotic pathway to their own ends. [ABSTRACT FROM AUTHOR]

Objective: Preeclampsia (PE) is characterized by systemic intravascular inflammation. Women who develop PE are at an increased risk for cardiovascular disease in later life. Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has anti-atherosclerotic effects in endothelial cells and can mediate neutrophil apoptosis. Low soluble TRAIL (sTRAIL) and high C-reactive protein (CRP) concentrations are associated with an increased risk of future cardiovascular disease in non-pregnant individuals. The aim of this study was to determine whether maternal plasma concentrations of sTRAIL and CRP differ between women with PE and those with uncomplicated pregnancies. Method: This cross-sectional study included women with an uncomplicated pregnancy ( n = 93) and those with PE ( n = 52). Maternal plasma concentrations of sTRAIL and CRP concentrations were determined by ELISA. Results: 1) The median plasma sTRAIL concentration (pg/mL) was significantly lower and the median plasma CRP concentration was significantly higher in women with PE than in those with an uncomplicated pregnancy (25.55 versus 29.17; p = 0.03 and 8.0 versus 4.1; p = 0.001, respectively); 2) the median plasma concentration sTRAIL/CRP ratio was two-fold lower in women with PE than in those with an uncomplicated pregnancy ( p < 0.001); and 3) women with plasma sTRAIL and CRP ratio in the lowest quartile were 8 times more likely to have PE than women with concentrations in the upper three quartiles (OR 8.9; 95% CI: 2.8-27.8). Conclusion: Maternal plasma sTRAIL concentrations are lower (while those of CRP are higher) in women with PE than in those with uncomplicated pregnancies. These findings are consistent with the evidence of intravascular inflammation in this disorder. [ABSTRACT FROM AUTHOR]

Neutrophil apoptosis is delayed in medical conditions associated to anoxia or hypoxia, prolonging tissue destruction and fostering the inflammation. Hypoxia Inducible Factor-1α (HIF-1α), is a main regulator of delayed neutrophil apoptosis but the mechanism of action is poorly characterized. Neutrophil gelatinase-associated lipocalin (24p3) participates actively in iron metabolism and the regulation of iron-responsive genes. Recently, a connection has been described between HIF-1α and 24p3. The purpose of the present study was to determine whether constitutive apoptosis in neutrophils requires 24p3 and whether HIF-1α represses 24p3 affecting cell death iron intracellular levels. To this end we used in vivo ischemic models and anoxic approaches based on the reactivation of the delayed apoptosis. We found that the stabilization of HIF-α during anoxic periods provoked a delay in neutrophil apoptosis through decrease of 24p3 expression and intracellular iron content. The ischemia drastically inhibited the synthesis of 24p3 in circulating neutrophils, increasing the tissue damage. Reactivation of neutrophil apoptosis with opsonized E.coli induced increases in intracellular levels of iron and 24p3. In conclusion, contrary to other cell types, constitutive apoptosis in neutrophils requires 24p3. During hypoxia or ischemia, HIF-1α stabilization represses 24p3 expression, consequently iron levels are depleted and neutrophil apoptosis is delayed. [ABSTRACT FROM AUTHOR]

Objective: Pregnancy is characterized by activation of the innate immune response demonstrated by phenotypic and metabolic changes in granulocytes and monocytes. This state of activation has been implicated in the pathophysiology of multiorgan dysfunction of pregnant women with acute viral or bacterial infection. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the mediators responsible for neutrophil apoptosis. Gene deletion of TRAIL results in delayed neutrophil apoptosis and resolution of inflammation after the administration of bacterial endotoxin. The aim of this study was to determine whether maternal plasma concentrations of the soluble form of TRAIL (sTRAIL) differ in women with uncomplicated pregnancy and those with acute pyelonephritis. Method: A cross-sectional study was conducted to include women in the following groups: (1) non-pregnant ( n = 23); (2) uncomplicated pregnancies ( n = 93) and (3) pregnancies with acute pyelonephritis ( n = 23). Plasma concentrations of sTRAIL were determined by enzyme-linked immunoassay. Results: (1) Women with uncomplicated pregnancies had a lower mean plasma sTRAIL concentration (pg/mL) than non-pregnant women (31.5 ± 10.1 versus 53.3 ± 12.5; p < 0.001); (2) plasma sTRAIL concentrations did not change as a function of gestational age (Pearson correlation = −0.1; p = 0.4); (3) the mean plasma sTRAIL concentration (pg/mL) was significantly lower in pregnant women with acute pyelonephritis than in those with uncomplicated pregnancies (20.5 ± 6.6 versus 31.5 ± 10.1; p < 0.001) and (4) among patients with acute pyelonephritis, patients with bacteremia had a significantly lower mean plasma concentration of sTRAIL (pg/mL) than those without bacteremia (15.1 ± 4.8 versus 24.7 ± 4.6; p < 0.001). Conclusion: Women with uncomplicated pregnancies are associated with a significantly lower mean maternal plasma concentration of sTRAIL than that observed in non-pregnant women. Moreover, a further decrease in plasma sTRAIL concentration was observed in pregnant women with acute pyelonephritis, and this could account, at least in part, for the exaggerated intravascular inflammatory response previously reported in pyelonephritis during pregnancy. [ABSTRACT FROM AUTHOR]

The authors report 9 cases of gastric carcinomas characterized by a prominent neutrophilic infiltration of the stroma. These tumors (8 of intestinal type, 1 of diffuse type) showed a pushing growth pattern. Metastatic involvement of regional lymph nodes was seen in 5 cases. The metastatic foci were associated with heavy neutrophilia as well. There was no histologic evidence of Helicobacter pylori infection, whereas various degrees of multifocal intestinal metaplasia were present in the background mucosa. Based on histologic and histochemical results, there were no apparent causes due to other infectious agents responsible for the neutrophil-rich gastric carcinomas. Some of intraepithelial and stromal neutrophils exhibited apoptotic changes, such as chromatin condensation and cell shrinkage, and were TUNEL-positive. Electron microscopy disclosed apoptotic neutrophils in cytoplasmic vacuoles of tumor cells, a finding suggestive of neutrophil-tumor cell phagocytosis (cannibalism). Different stages of neutrophil apoptosis were also shown by electron microscopy and the ultrastructural findings were compared to those described in experimental models, both in vivo and in vitro. [ABSTRACT FROM AUTHOR]

The recognition and removal of apoptotic inflammatory cells by tissue macrophages and non-professional phagocytes, in a process called efferocytosis, is required for resolution of inflammation and is actively anti-inflammatory. We have previously demonstrated phagocytosis of apoptotic neutrophils by tumor cells in human gastric carcinoma, but to date, there have been no studies investigating this process in chronic active Helicobacter pylori gastritis. Biopsy specimens from 28 subjects with or without H. pylori infection and active inflammation were examined and graded according to the updated Sydney system. Light microscopy, electron microscopy, and Terminal Deoxynucleotidyltransferase-Mediated UTP End Labeling staining were used to identify apoptosis. H. pylori infection was detected by histology and by molecular assay in 16 out of 28 cases. DNA from paraffin-embedded gastric biopsies was amplified using primers specific for cagA, for the cag 'empty site' as well as for the s and m alleles of vacA. The more virulent cagA-positive strains were found in five out of nine patients with chronic active gastritis. The vacA s1/m1 and s2/m1 genotypes were more common in nine patients with chronic active gastritis, while the vacA s2/m2 genotype was more frequent in seven patients with chronic inactive gastritis. Apoptotic neutrophils were also detected within the cytoplasmic vacuoles of the foveolar cells of nine cases with chronic active gastritis. Transmission electron micrographs revealed further apoptotic neutrophils within spacious phagosomes of foveolar cells in a similar manner to those described in late-phase efferocytosis both in vivo and in vitro. These new observations expand the morphological spectrum of gastritis in patients infected with more virulent H. pylori strains, compatible with an anti-inflammatory role for the gastric epithelial cells in their removal of apoptotic neutrophils during active chronic gastritis. [ABSTRACT FROM AUTHOR]

Autosomal recessive severe congenital neutropenia (SCN) results from a maturation arrest of granulopoiesis at the level of promyelocytes and apoptosis of myeloid cells. In SCN patients, mutations have been described in the HAX1 gene. Most of the SCN patients who carry nonsense mutations that are common to both transcript variants of the HAX1 gene also exhibit neurological deficits. This study describes an SCN patient with neurological manifestations including daily episodes of atonic seizures, learning disabilities, and developmental delay. Sequencing of the HAX1 gene of this SCN patient identified a novel nonsense c.463_464insC homozygous mutation in exon 3, which is common to both transcript variants of the gene. This mutation encodes for a p.Gln155ProfsX14 change and causes premature truncation of the HAX1 protein. Neutrophils isolated from the patient exhibited spontaneous apoptosis and loss of inner mitochondrial membrane potential, which were further enhanced upon treatment with hydrogen peroxide. This study adds to the spectrum of novel HAX1 gene mutations and disease manifestations in ethnically distinct SCN patients. Our report describes the only nonsense mutation in the HAX1 gene present in SCN patients of Arab origin. [ABSTRACT FROM AUTHOR]

Polymorphonuclear neutrophilic leukocytes (PMNL) play an important role in the first line cell-mediated immune defense of the body in general and of the mammary gland against mastitis pathogens in particular. Reduced viability of PMNL close to parturition may explain the high incidence of infectious diseases and the high prevalence of intramammary infections (IMI) in periparturient dairy heifers. Apoptosis of blood PMNL 1 wk before the expected calving date and of blood and milk PMNL at 1 to 4 d in milk was determined using flow cytometry. Information on heifer and gland characteristics was collected before calving and in early lactation. Data were analyzed using multivariable, multilevel regression analysis. Supplementation of a commercial mineral/vitamin mix before calving was associated with less blood (14.4 ± 2.9 vs. 22.4 ± 2.1%) and milk PMNL apoptosis (19.0 ± 1.1 vs. 26.4 ± 0.9%) near calving, presumably related to higher blood selenium concentrations. Both blood and milk PMNL apoptosis showed seasonal variation with the highest proportion of apoptotic cells between January and March (32.0 ± 6.1 and 34.6 ± 2.7%, respectively) and April and June (31.3 ± 5.7 and 37.8 ± 2.3%, respectively). Heifers losing 0.25 points or more of their body condition in the periparturient period had higher proportions of apoptotic blood PMNL in early lactation compared with heifers losing less than 0.25 points (24.0 ± 2.8 vs. 16.6 ± 1.7%). Milk PMNL apoptosis was less pronounced in quarters having teat orifices colonized with non-aureus staphylococci before calving (18.9 ± 1.0 vs. 29.4 ± 1.0%). The variation in blood PMNL apoptosis before and after calving mainly resided at the heifer level (71.4 and 98.4% of the total variation, respectively), whereas the variation in milk PMNL apoptosis mainly resided at the heifer (45.7% of the total variation) and quarter levels (45.5% of the total variation). These data imply that the impaired blood and milk PMNL viability in periparturient heifers can be reduced by optimization of certain heifer management practices such as supplementation of minerals/vitamins, and pasture and feeding strategies. [ABSTRACT FROM AUTHOR]

Aims: Congestive heart failure (CHF) can be thought of as a state of chronic immune activation. Polymorphonuclear neutrophil (PMN) apoptosis is one of the mechanisms responsible for the resolution of inflammation. A reduced PMN apoptotic rate in CHF patients may generate a persistent inflammatory response and hence mediate tissue damage in this group of patients. We aimed to measure levels of spontaneous apoptosis of circulating PMNs in CHF patients and in controls, and to examine whether NYHA class, left ventricular ejection fraction (LV-EF), and laboratory parameters of inflammation, endothelial damage, and of liver and renal function, could predict the rate of PMN apoptosis in CHF patients. [ABSTRACT FROM PUBLISHER]

Pegfilgrastim is a covalent conjugate of filgrastim and polyethylene glycol that has proved to be effective in supporting myelopoiesis during chemotherapy. Since very limited information is available on the biological effects of pegfilgrastim on neutrophils exposed to chemotherapy, we analyzed the following parameters in neutrophils of patients undergoing dose-dense chemotherapy for breast cancer: apoptosis, by a TUNEL technique; actin polymerization, using FITC-labeled phalloidin, and alkaline phosphatase activity by cytochemistry. Peripheral blood buffy coat smears were obtained before starting treatment and immediately before each chemotherapy course. After pegfilgrastim stimulation we observed the following: (1) stability of the absolute neutrophil count for the whole duration of treatment and no infectious events; (2) a reduction in the neutrophil constitutive apoptosis rate in comparison with that observed in control patients treated with standard chemotherapy courses with no growth factor support; (3) persistent abnormalities of actin assembly in neutrophils, indicative of changes in cytoskeletal organization, and (4) a significant increase in the activity of leukocyte alkaline phosphatase, a sensitive marker of the later stages of neutrophil maturation. In conclusion, these results suggest that pegfilgrastim improves the neutrophil functions in patients exposed to chemotherapy by inhibition of constitutive apoptosis, thereby prolonging the survival of these cells. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLRs) play a critical role in the induction of the immune response to invading pathogens. The detection of pathogens by TLRs initiates a signalling cascade that results in the activation of transcription factors such as nuclear factor (NF)- κB and interferon regulatory factors leading to the production of pro-inflammatory cytokines and type 1 interferons. Five cytoplasmic adaptors, MyD88, Mal, Trif, TRAM and SARM, are utilized by the TLRs to activate these signalling pathways. Through the years the main focus of research has been on the activation and function of TLRs in monocytic cells. This review discusses several additional roles of TLRs. TLR activation plays a role in influencing the differentiation of haematopoietic stem cells. Their activation also prevents apoptosis in neutrophils following pathogen invasion. B cells and T cells proliferation and differentiation is influenced by TLR activation and the possible therapeutic benefits of using TLR ligands for the treatment of chronic lymphocytic leukaemia will also be discussed. [ABSTRACT FROM AUTHOR]

Background:Despite antibiotic treatment, the mortality of severe community-acquired pneumonia (CAP), especially in patients with severe comorbidity, remains high. Innate defense mechanisms including polymorphonuclear neutrophil (PMN) activation and survival, orchestrated by cytokines, are primarily responsible for the elimination of bacterial organisms from the alveolus. Objectives: The aim of this study was to evaluate the effect of granulocyte colony-stimulating factor (G-CSF) on PMN activation, apoptosis and cytokine response in patients with CAP. Methods: Patients received a single dose of G-CSF (1 × 300 or 480 μg s.c.) prior to standard antibiotic treatment (n = 8) or standard treatment only (n = 8). Apoptosis rate and expression of CD11b, CD66b, CD64 and CD114 surface molecules on systemic PMN were assessedusing fluorescence-activated cell sorter analysis. Levels of the interleukin-1 receptor antagonist (IL-1RA), the soluble tumor necrosis factor receptor inhibitor (sTNF-p55) and G-CSF were measured by ELISA. Results: In the treatment group, 12 h after G-CSF application, neutrophil count increased, neutrophil activation marker CD11b was stimulated (CD11b: 48.6 ± 9.7 vs. 71.2 ± 17.7, p < 0.01), neutrophil apoptosis decreased (apoptosis: 1.36 ± 0.27 vs. 0.2 ± 0.12%, p < 0.01) and the concentration of IL-1RA and sTNF-p55 increased (IL-1RA 136.4 ± 72.2 vs. 340.1 ± 194.6 ng/ml, p < 0.01; sTNF-p55 382 ± 4,243 vs. 632 ± 4,714 ng/ml, p < 0.01; control group nonsignificant). These effects were not seen in the control group. Conclusions: The application of a single dose of G-CSF in patients with CAP caused a prolonged survival and increased activation of neutrophils combined with a sustained release of anti-inflammatory cytokines. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Delayed neutrophil apoptosis has been implicated as the mechanism of the systemic inflammatory response. Herein, we examined the effect of melatonin on the neutrophil apoptosis in ischemia and reperfusion of the human liver. We studied seven patients receiving elective hepatectomy for liver tumor and ten patients receiving laparoscopic cholecystectomy for gallstones. Ten milli liters of blood was drawn isolation and incubation of the human neutrophils. Neutrophil apoptosis activity and CD18 expression and respiratory burst activity were assessed flow cytometrically. Another group of neutrophils included those from the patients receiving hepatectomy and isolated and incubated with melatonin. Neutrophil apoptosis is delayed from patients after hepatectomy or laparoscopic cholecystectomy when compared with that of the preoperative state. The decrease in the apoptosis activity is more severe in patients receiving hepatectomy as compared with those receiving laparoscopic cholecystectomy. Neutrophils from patients receiving hepatectomy or laparoscopic cholecystectomy are functionally activated. Melatonin can reverse the delayed process and enhance the apoptosis activity in neutrophils from patients receiving hepatectomy. This study demonstrates that melatonin enhances neutrophil apoptosis in patients receiving hepatectomy involving ischemia and reperfusion of the human liver. [ABSTRACT FROM AUTHOR]

Apoptosis, or programmed cell death, has been reported to play an important role in the resolution of pulmonary inflammation. This study was undertaken to investigate the role of apoptosis in resolving particle-induced lung inflammatory responses in exposed rats, using a dose-response / time course experimental design. Groups of rats were exposed via intratracheal instillation to 0, 0.5, 1, 5, 10, or 50 mg/kg body weight of quartz (i.e., crystalline silica) particles or to 0, 0.5, 1, 5, 10, 20, or 50 mg/kg of pigment-grade titanium dioxide (TiO[sub 2]) particles and evaluated for lung inflammation parameters and evidence of apoptosis of inflammatory cells at 24, 48, 72, or 168 hours post exposure. At each post exposure evaluation period, bronchoalveolar lavage (BAL)-recovered cells from control and particle-exposed rats were assessed for apoptosis using 4 different techniques. The results in silica-exposed rats demonstrated a significant dose-related increase in inflammation concomitant with apoptosis of pulmonary inflammatory cells at 24 to 48 hours post exposure. At later postexposure time points, both the silica-induced inflammatory responses and apoptotic levels of inflammatory cells at higher doses (i.e., ≥ 5 mg/kg) were reduced but persisted through 1 week. TUNEL (TdT-mediated dUTP nick end-labeling) assay studies confirmed that the vast majority of apoptotic cells were neutrophils. In contrast, titanium dioxide particle exposures produced transient pulmonary inflammation but only small measurable and nonsignificant apoptotic responses at higher exposure concentrations. These results suggest that the sustained lung inflammatory response in rats exposed to ≥ 5 mg/kg silica may be related to the ineffectiveness of the normal apoptotic mechanisms associated with resolution of inflammation. However, because quartz particles are known to be cytotoxic to alveolar macrophages and other lung cells, normal apoptotic mechanisms may have limited utility for resolving particle-induced inflammation, particularly because silica may not be representative of other particle-types. Alternatively, it seems unlikely that apoptosis served to promote silica-induced lung inflammatory responses because the initial increase of apoptosis in inflammatory cells was subsequently correlated with a reduction of the pulmonary inflammatory response in silica-exposed rats. The findings from this in vivo study demonstrate that the neutrophil, and not the alveolar macrophage, is the primary inflammatory cell-type that undergoes apoptosis in response to particles. Furthermore, at doses causing similar degrees of inflammation at 24 hours post exposure, the magnitude of apoptosis induced by silica is significantly larger than that induced by TiO[sub 2], indicating that there are potency differences in lung inflammation as well as apoptotic responses among different particle-types. [ABSTRACT FROM AUTHOR]