Neutrophil activity in sepsis: a systematic review.

The neutrophil is an important cell in host defense against infections, acting as the first line of microorganism control. However, this cell exhibits dysregulated activity in sepsis and may contribute to the pathogenesis of the disease. This systematic review aimed to highlight the major scientific findings regarding neutrophil activity in sepsis reported in clinical and experimental research published in the last 10 years. The search was conducted in the Virtual Health Library of PAHO-WHO (BVS) and PubMed databases, and articles published between January 2007 and May 2017 in Portuguese, English, and Spanish were eligible. Article selection was carried out independently by two reviewers (CB and IB). A total of 233 articles were found, of which 87 were identified on PubMed and 146 on BVS. Eighty-two articles were duplicates. Of the remaining 151 articles, 19 met the inclusion criteria after title, abstract, and full-text analysis. Overall, research in clinical samples and animal models of sepsis showed reduced capacity of neutrophils to migrate and delayed apoptosis, but there was no consensus on the phagocytic activity of neutrophils in sepsis. Molecules, such as pentraxin 3 (PTX3), have been analyzed as potential diagnostic markers in sepsis but the diversity of soluble molecules detected in blood samples of sepsis patients did not enable further understanding of the correlation of these circulating molecules with neutrophil activity during sepsis. Optimal understanding of the function of neutrophils in sepsis remains a challenge that, if overcome, would eventually allow targeted therapeutic interventions in patients affected by this severe syndrome.

Neutrophil activity in sepsis: a systematic review

The neutrophil is an important cell in host defense against infections, acting as the first line of microorganism control. However, this cell exhibits dysregulated activity in sepsis and may contribute to the pathogenesis of the disease. This systematic review aimed to highlight the major scientific findings regarding neutrophil activity in sepsis reported in clinical and experimental research published in the last 10 years. The search was conducted in the Virtual Health Library of PAHO-WHO (BVS) and PubMed databases, and articles published between January 2007 and May 2017 in Portuguese, English, and Spanish were eligible. Article selection was carried out independently by two reviewers (CB and IB). A total of 233 articles were found, of which 87 were identified on PubMed and 146 on BVS. Eighty-two articles were duplicates. Of the remaining 151 articles, 19 met the inclusion criteria after title, abstract, and full-text analysis. Overall, research in clinical samples and animal models of sepsis showed reduced capacity of neutrophils to migrate and delayed apoptosis, but there was no consensus on the phagocytic activity of neutrophils in sepsis. Molecules, such as pentraxin 3 (PTX3), have been analyzed as potential diagnostic markers in sepsis but the diversity of soluble molecules detected in blood samples of sepsis patients did not enable further understanding of the correlation of these circulating molecules with neutrophil activity during sepsis. Optimal understanding of the function of neutrophils in sepsis remains a challenge that, if overcome, would eventually allow targeted therapeutic interventions in patients affected by this severe syndrome.

Alemtuzumab as graft-versus-host disease (GVHD) prophylaxis strategy in a developing country: lower rate of acute GVHD, increased risk of cytomegalovirus reactivation.

Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2-4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2-4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival.

Alemtuzumab as graft-versus-host disease (GVHD) prophylaxis strategy in a developing country: lower rate of acute GVHD, increased risk of cytomegalovirus reactivation

Acute graft-versus-host disease (aGVHD) and cytomegalovirus reactivation are important complications after allogeneic stem cell transplantation (alloHSCT). Here, we evaluated the impact of treatment with alemtuzumab on the occurrence of aGVHD, cytomegalovirus reactivation and survival after alloHSCT. This was a prospective cohort study conducted at the allo-HSCT unit of Hospital das Clínicas, Universidade Federal de Minas Gerais, Brazil, from January 2009 to December 2011. Fifty-seven patients who underwent alloHSCT were included. Forty-five (79%) patients had a malignant disease. Alemtuzumab was administered before the conditioning regimen at a dose of 1 mg/kg in children and 30 mg/day for 2 days in adults or children weighing more than 40 kg (a total dose of 60 mg) with a non-malignant disease or patients with a malignant disease and high-risk for GVHD mortality. Alemtuzumab was used in 23 (40%) patients, of whom 17 received a reduced-intensity conditioning. Eleven patients presented aGVHD (grade 2–4) and only 1 of them received alemtuzumab. Cumulative incidence of aGVHD (grade 2–4) at day 100 after transplantation (D+100) was 4 for patients receiving alemtuzumab and 29% for patients not receiving alemtuzumab. Cumulative incidence of cytomegalovirus reactivation for patients receiving or not alemtuzumab was 62 and 38%, respectively. Sixteen patients died in the first 100 days after alloHSCT, most of them due to bacterial sepsis. Only 2 patients died of aGVHD until D+100. Overall survival was 50% without any impact of alemtuzumab. Alemtuzumab effectively controlled aGVHD but increased the risk of cytomegalovirus reactivation without improving survival.

Induction of eosinophil apoptosis by hydrogen peroxide promotes the resolution of allergic inflammation.

Eosinophils are effector cells that have an important role in the pathogenesis of allergic disease. Defective removal of these cells likely leads to chronic inflammatory diseases such as asthma. Thus, there is great interest in understanding the mechanisms responsible for the elimination of eosinophils from inflammatory sites. Previous studies have demonstrated a role for certain mediators and molecular pathways responsible for the survival and death of leukocytes at sites of inflammation. Reactive oxygen species have been described as proinflammatory mediators but their role in the resolution phase of inflammation is poorly understood. The aim of this study was to investigate the effect of reactive oxygen species in the resolution of allergic inflammatory responses. An eosinophilic cell line (Eol-1) was treated with hydrogen peroxide and apoptosis was measured. Allergic inflammation was induced in ovalbumin sensitized and challenged mouse models and reactive oxygen species were administered at the peak of inflammatory cell infiltrate. Inflammatory cell numbers, cytokine and chemokine levels, mucus production, inflammatory cell apoptosis and peribronchiolar matrix deposition was quantified in the lungs. Resistance and elastance were measured at baseline and after aerosolized methacholine. Hydrogen peroxide accelerates resolution of airway inflammation by induction of caspase-dependent apoptosis of eosinophils and decrease remodeling, mucus deposition, inflammatory cytokine production and airway hyperreactivity. Moreover, the inhibition of reactive oxygen species production by apocynin or in gp91(phox-/-) mice prolonged the inflammatory response. Hydrogen peroxide induces Eol-1 apoptosis in vitro and enhances the resolution of inflammation and improves lung function in vivo by inducing caspase-dependent apoptosis of eosinophils.

Astaxanthin diferulate as a bifunctional antioxidant.

Astaxanthin when esterified with ferulic acid is better singlet oxygen quencher with k2 = (1.58 ± 0.1) 10(10) L mol(-1)s(-1) in ethanol at 25°C compared with astaxanthin with k2 = (1.12 ± 0.01) 10(9) L mol(-1)s(-1). The ferulate moiety in the astaxanthin diester is a better radical scavenger than free ferulic acid as seen from the rate constant of scavenging of 1-hydroxyethyl radicals in ethanol at 25°C with a second-order rate constant of (1.68 ± 0.1) 10(8) L mol(-1)s(-1) compared with (1.60 ± 0.03) 10(7) L mol(-1)s(-1) for the astaxanthin:ferulic acid mixture, 1:2 equivalents. The mutual enhancement of antioxidant activity for the newly synthetized astaxanthin diferulate becoming a bifunctional antioxidant is rationalized according to a two-dimensional classification plot for electron donation and electron acceptance capability.

Enalapril prevents cardiac immune-mediated damage and exerts anti-Trypanosoma cruzi activity during acute phase of experimental Chagas disease.

Chagas heart disease (CHD), caused by Trypanosoma cruzi infection, is a significant cause of morbidity and mortality in South and Central America. Enalapril, an angiotensin converting enzyme (ACE) inhibitor, is an important drug used to ameliorate heart functional capacity and its remodelling in individuals presenting CHD. In this study, we evaluated the effects of enalapril on systemic and cardiac immune response during experimental acute CHD. C57BL/6 mice infected with 50 trypomastigote forms of T. cruzi (Colombian strain) were treated daily with enalapril (25 mg/kg) and, after 30 days, a reduction in seric levels of IFN-gamma, TNF-alpha, CCL5/RANTES and nitric oxide, but not in that of IL-10, was detected. This imbalance of cytokines reflects in a reduction of heart mononuclear infiltration and in an increasing of cardiac mast cells. Enalapril also presents a new and interesting in vitro and in vivo anti-T. cruzi activity probably acting on parasite oxidative pathway via cytochrome-P450. Our data show that enalapril exerts an important anti-T. cruzi and anti-inflammatory activity during acute CHD reducing inflammatory cells and, possibly, preventing fibrotic process in the chronic phase. Nevertheless, further studies are still necessary to clarify the mechanisms by which this drug is acting on the parasites and on the immune pathways.

Impaired host defense to Klebsiella pneumoniae infection in mice treated with the PDE4 inhibitor rolipram.

The increase in levels of cAMP in leukocytes by selective inhibitors of PDE4 may result in reduction of inflammation, and may be useful in the treatment of pulmonary inflammatory disorders in humans. Here, we have assessed whether oral treatment with the prototype PDE4 inhibitor, rolipram, interfered with the antibacterial host response following pulmonary infection of mice with Klebsiella pneumoniae. K. pneumoniae infection induced a marked increase in the recruitment of neutrophils to the lungs and the production of proinflammatory cytokines and chemokines, including tumor necrosis factor-alpha (TNF-alpha) and keratinocyte-derived chemokine (KC), in bronchoalveolar (BAL) fluid and lung tissue. There were also detectable amounts of interleukin-10 (IL-10) and significant lethality. Treatment with rolipram (3-30 mg kg-1) was associated with earlier lethality and significant inhibition of the TNF-alpha production. This was associated with enhanced production of IL-10 in lung tissue of rolipram-treated animals. Rolipram treatment did not affect KC expression and the recruitment of neutrophils in the lung tissue. Over 70% of neutrophils that migrated into the BAL fluid following K. pneumoniae infection ingested bacteria. Treatment with rolipram inhibited the percentage of neutrophils undergoing phagocytosis of K. pneumoniae in a dose-dependent manner. Maximal inhibition (62%) occurred at doses equal to or greater than 10 mg kg-1. Thus, treatment of mice with the PDE4 inhibitor rolipram is accompanied by earlier lethality, enhanced bacterial load and decreased capacity of the responding host to produce TNF-alpha and of neutrophils to phagocytose bacteria. It will be important to investigate whether the shown ability of PDE4 inhibitors to inhibit neutrophil phagocytosis and control experimental bacterial infection will translate into an inhibition of the ability of neutrophils to deal with infectious microorganisms in the clinical setting.

Role of the platelet-activating factor (PAF) receptor during pulmonary infection with gram negative bacteria.

The lipid mediator PAF plays an important role in the phagocytosis of particles, including bacteria, and consequent production of pro-inflammatory cytokines, such as TNF-alpha and IL-8. Using a PAF receptor antagonist (UK-74,505) and PAF receptor knock-out mice, we have investigated the relevance of PAF for the inflammatory changes and lethality after pulmonary infection with the gram-negative bacteria Klebsiella pneumoniae in mice. At an inoculum of 3 x 10(6) bacteria, there was marked pulmonary (bronchoalveolar lavage and lung) neutrophilia that started early (2.5 h after infection) and peaked at 48 h. All animals were dead by day 4 of infection. The chemokine KC and the pro-inflammatory cytokine TNF-alpha increased rapidly and persisted for 48 h in the lungs. Pretreatment with UK-74,505 (30 mg kg(-1) per day, p.o.) had no significant effects on the number of infiltrating neutrophils in BAL fluid or lung tissue, as assessed by histology and measuring myeloperoxidase, or on the concentrations of KC. In contrast, concentrations of TNF-alpha and the number of bacteria inside neutrophils were significantly diminished. In order to support a role for the PAF during K. pneumoniae infection, experiments were also carried out in PAFR-deficient mice. In the latter animals, lethality occurred earlier than in wild-type controls. This was associated with greater number of bacteria in lung tissue and diminished percentage of neutrophils containing bacteria in their cytoplasm. Our results suggest that PAF, acting on its receptor, plays a protective role during infection with K. pneumoniae in mice.