CFTR is required for zinc-mediated antibacterial defense in human macrophages.

Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion transporter required for epithelial homeostasis in the lung and other organs, with mutations leading to the autosomal recessive genetic disease CF. Apart from excessive mucus accumulation and dysregulated inflammation in the airways, people with CF (pwCF) exhibit defective innate immune responses and are susceptible to bacterial respiratory pathogens such as . Here, we investigated the role of CFTR in macrophage antimicrobial responses, including the zinc toxicity response that is used by these innate immune cells against intracellular bacteria.

Azithromycin Augments Bacterial Uptake and Anti-Inflammatory Macrophage Polarization in Cystic Fibrosis.

Background: Azithromycin (AZM) is widely being used for treating patients with cystic fibrosis (pwCF) following clinical trials demonstrating improved lung function and fewer incidents of pulmonary exacerba-tions. While the precise mechanisms remain elusive, immunomodulatory actions are thought to be involved. We previously reported impaired phagocytosis and defective anti-inflammatory M2 macrophage polarization in CF.

Cytotoxic and Bactericidal Effects of Inhalable Ciprofloxacin-Loaded Poly(2-ethyl-2-oxazoline) Nanoparticles with Traces of Zinc Oxide.

The bactericidal effects of inhalable ciprofloxacin (CIP) loaded-poly(2-ethyl-2-oxazoline) (PEtOx) nanoparticles (NPs) with traces of zinc oxide (ZnO) were investigated against clinical strains of the respiratory pathogens and CIP-loaded PEtOx NPs retained their bactericidal activity within the formulations compared to free CIP drugs against these two pathogens, and bactericidal effects were enhanced with the inclusion of ZnO. PEtOx polymer and ZnO NPs did not show bactericidal activity alone or in combination against these pathogens. The formulations were tested to determine the cytotoxic and proinflammatory effects on airway epithelial cells derived from healthy donors (NHBE), donors with chronic obstructive pulmonary disease (COPD, DHBE), and a cell line derived from adults with cystic fibrosis (CFBE41o-) and macrophages from healthy adult controls (HCs), and those with either COPD or CF.

Anti-inflammatory effects of lenabasum, a cannabinoid receptor type 2 agonist, on macrophages from cystic fibrosis.

Background: Lenabasum is an oral synthetic cannabinoid receptor type 2 agonist previously shown to reduce the production of key airway pro-inflammatory cytokines known to play a role in cystic fibrosis (CF). In a double-blinded, randomized, placebo-control phase 2 study, lenabasum lowered the rate of pulmonary exacerbation among patients with CF. The present study was undertaken to investigate anti-inflammatory mechanisms of lenabasum exhibits in CF macrophages.

TLR Crosstalk Activates LRP1 to Recruit Rab8a and PI3Kγ for Suppression of Inflammatory Responses.

The multi-ligand endocytic receptor, low-density lipoprotein-receptor-related protein 1 (LRP1), has anti-inflammatory roles in disease. Here, we reveal that pathogen-activated Toll-like receptors (TLRs) activate LRP1 in human and mouse primary macrophages, resulting in phosphorylation of LRP1 at Y4507. In turn, this allows LRP1 to activate and recruit the guanosine triphosphatase (GTPase), Rab8a, with p110γ/p101 as its phosphatidylinositol 3-kinase (PI3K) effector complex.

Differential expression of genes and receptors in monocytes from patients with cystic fibrosis.

Introduction: We previously reported defective alternative polarization (M2) of macrophages and early expression of classically polarized (M1) macrophage markers in unpolarized monocyte-derived macrophages (MDMs) in patients with cystic fibrosis (CF). The present study assessed whether the mechanism(s) underlying defective macrophage polarization resided in circulating monocytes.

Methods: Monocyte subsets (classical, intermediate and non-classical), markers for monocyte activation (CD163) and recruitment (CD195), receptors/genes associated with macrophage differentiation and polarization were analyzed in CF and compared with healthy individuals.

CFTR-dependent defect in alternatively-activated macrophages in cystic fibrosis.

Background: The role of the macrophages in cystic fibrosis (CF) lung disease has been poorly studied. We hypothesized that alternatively activated M2 macrophages are abnormal in CF lung disease.

Methods: Blood samples were collected from adults (n=13) children (n=27) with CF on admission for acute pulmonary exacerbation and when clinically stable.

Phenotypic, functional, and plasticity features of classical and alternatively activated human macrophages.

Macrophages are dynamic cells that mature under the influence of signals from the local microenvironment into either classically (M1) or alternatively (M2) activated macrophages with specific functional and phenotypic properties. Although the phenotypic identification of M1 and M2 macrophages is well established in mice, this is less clear for human macrophages. In addition, the persistence and reversibility of polarized human phenotypes is not well established.

Immunization of mice with vibrio cholerae outer-membrane vesicles protects against hyperinfectious challenge and blocks transmission.

Background: Vibrio cholerae excreted by cholera patients is "hyperinfectious" (HI), which can be modeled by passage through infant mice. Immunization of adult female mice with V. cholerae outer-membrane vesicles (OMVs) passively protects suckling mice from challenge.

Zinc influences innate immune responses in children with enterotoxigenic Escherichia coli-induced diarrhea.

Information is limited on the effect of zinc on immune responses in children with diarrhea due to enterotoxigenic Escherichia coli (ETEC), the most common bacterial pathogen in children. We studied the immunological effect of zinc treatment (20 mg/d) and supplementation (10 mg/d) in children with diarrhea due to ETEC. A total of 148 children aged 6-24 mo were followed up for 9 mo after a 10-d zinc treatment (ZT; n = 74) or a 10-d zinc treatment plus 3-mo supplementation (ZT+S; n = 74), as well as 50 children with ETEC-induced diarrhea that were not treated with zinc (UT).

Development of immunoglobulin M memory to both a T-cell-independent and a T-cell-dependent antigen following infection with Vibrio cholerae O1 in Bangladesh.

Vibrio cholerae O1 can cause severe watery diarrhea that can be life-threatening without treatment. Infection results in long-lasting protection against subsequent disease. Development of memory B cells of the immunoglobulin G (IgG) and IgA isotypes to V.

Comparative proteomic analysis of the PhoP regulon in Salmonella enterica serovar Typhi versus Typhimurium.

Background: S. Typhi, a human-restricted Salmonella enterica serovar, causes a systemic intracellular infection in humans (typhoid fever). In comparison, S.

Memory T-cell responses to Vibrio cholerae O1 infection.

Vibrio cholerae O1 can cause diarrheal disease that may be life-threatening without treatment. Natural infection results in long-lasting protective immunity, but the role of T cells in this immune response has not been well characterized. In contrast, robust B-cell responses to V.

Enhanced immunogenicity of an oral inactivated cholera vaccine in infants in Bangladesh obtained by zinc supplementation and by temporary withholding breast-feeding.

The killed oral cholera vaccine Dukoral is recommended for adults and only children over 2 years of age, although cholera is seen frequently in younger children and there is an urgent need for a vaccine for them. Since decreased immunogenicity of oral vaccines in children in developing countries is a critical problem, we tested interventions to enhance responses to Dukoral. We evaluated the effect on the immune responses by temporarily withholding breast-feeding or by giving zinc supplementation.

Disease burden due to enterotoxigenic Escherichia coli in the first 2 years of life in an urban community in Bangladesh.

A cohort of 321 children was followed from birth up to 2 years of age to determine the incidence of enterotoxigenic Escherichia coli (ETEC) in Bangladesh. The average number of diarrheal days and incidence rates were 6.6 and 2.

Peru-15, a live attenuated oral cholera vaccine, is safe and immunogenic in Bangladeshi toddlers and infants.

A live oral Vibrio cholerae O1 El Tor vaccine, Peru-15 was tested in a double-blind, randomized placebo controlled study for safety and immunogenicity in Phase I and Phase II studies in 240 Bangladeshi children aged 9 months-5 years of age. Two different doses (2x10(7) and 2x10(8)cfu) were tested. Vaccination did not elicit adverse events and the strain was genetically stable.

Two New Compounds from the Galls of Quercus infectoria. with Nitric Oxide and Superoxide Inhibiting Ability.

Two compounds isolated from the ethanol extract of the galls of Quercus infectoria. Olivier exhibited nitric oxide (NO) and superoxide [Formula: see text] inhibiting activity. Their structures were established as ellagic acid-4-O.

Terminoside A, a new triterpene glycoside from the bark of Terminalia arjuna inhibits nitric oxide production in murine macrophages.

Terminoside A (1), a new oleanane-type triterpene was isolated from the acetone fraction of the ethanolic extract of stem bark of Terminalia arjuna. The structure was established as olean-1alpha,3beta,22beta-triol-12-en-28-oic acid-3beta-D-glucopyranoside. On the basis of spectral data and chemical reactions, terminoside A, potently inhibited nitric oxide (NO) production and decreased inducible nitric oxide synthase (iNOS) levels in lipopolysaccharide-stimulated macrophages.