Alveolar inflammation in cystic fibrosis

In infected lungs of the cystic fibrosis (CF) patients, opportunistic pathogens and mutated cystic fibrosis transmembrane conductance regulator protein (CFTR) contribute to chronic airway inflammation that is characterized by neutrophil/macrophage infiltration, cytokine release and ceramide accumulation. We sought to investigate CF lung inflammation in the alveoli.

Relating the physicochemical characteristics and dispersion of multiwalled carbon nanotubes in different suspension media to their oxidative reactivity in vitro and inflammation in vivo

Reactive oxygen species (ROS) production is important in the toxicity of pathogenic particles such as fibres. We examined the oxidative potential of straight (50 microm and 10 microm) and tangled carbon nanotubes in a cell free assay, in vitro and in vivo using different dispersants. The cell free oxidative potential of tangled nanotubes was higher than for the straight fibres. In cultured macrophages tangled tubes exhibited significantly more ROS at 30 min, while straight tubes increased ROS at 4 h. ROS was significantly higher in bronchoalveolar lavage cells of animals instilled with tangled and 10 mum straight fibres, whereas the number of neutrophils increased only in animals treated with the long tubes. Addition of dispersants in the suspension media lead to enhanced ROS detection by entangled tubes in the cell-free system. Tangled fibres generated more ROS in a cell-free system and in cultured cells, while straight fibres generated a slower but more prolonged effect in animals.

Prolonged inflammation following critical illness may impair long-term survival: a hypothesis with potential therapeutic implications

Despite successful intensive care a substantial portion of critically ill patients dies after discharge from the intensive care unit or hospital. Observational studies investigating long-term survival of critically ill patients reported that most deaths occur during the first months or year after discharge. Only limited data on the causes of impaired quality of life and post-intensive care unit deaths exist in the current literature. In this manuscript we hypothesize that the acute inflammatory response which characteristically accompanies critical illness is ensued by a prolonged imbalance or activation of the immune system. Such a chronic low-grade inflammatory response to critical illness may be sub-clinical and persist for a variable period of time after discharge from the intensive care unit and hospital. Chronic inflammation is a well-recognized risk factor for long-term morbidity and mortality, particularly from cardiovascular causes, and may thus partly contribute to the impaired quality of life as well as increased morbidity and mortality following intensive care unit and hospital discharge of critically ill patients. Assuming that critical illness is indeed followed by a prolonged inflammatory response, important implications for treatment would arise. An interesting and potentially beneficial therapy could be the administration of immune-modulating drugs during the time after intensive care unit or hospital discharge until chronic inflammation has subsided. Statins are well-investigated and effective drugs to attenuate chronic inflammation and could potentially also improve long-term outcome of critically ill patients after intensive care unit or hospital discharge. Future studies evaluating the course of inflammation during and after critical illness as well as its response to statin therapy are required.

Heart rate variability and biomarkers of systemic inflammation in patients with stable coronary heart disease: findings from the Heart and Soul Study

Chronic low-grade systemic inflammation is a key component in atherogenesis. Decreased heart rate variability (HRV), a strong predictor of cardiovascular events, has been associated with elevations in circulating levels of C-reactive protein (CRP), interleukin (IL)-6, and fibrinogen in apparently healthy individuals. We investigated whether decreased HRV is associated with inflammatory markers in patients with coronary heart disease (CHD).

Fas-activated serine/threonine phosphoprotein promotes immune-mediated pulmonary inflammation

We generated Fas-activated serine threonine phosphoprotein (FAST)-deficient mice (FAST(-/-)) to study the in vivo role of FAST in immune system function. In a model of house dust mite-induced allergic pulmonary inflammation, wild type mice develop a mixed cellular infiltrate composed of eosinophils, lymphocytes, and neutrophils. FAST(-/-) mice develop airway inflammation that is distinguished by the near absence of neutrophils. Similarly, LPS-induced alveolar neutrophil recruitment is markedly reduced in FAST(-/-) mice compared with wild type controls. This is accompanied by reduced concentrations of cytokines (TNF-alpha and IL-6 and -23) and chemoattractants (MIP-2 and keratinocyte chemoattractant) in bronchoalveolar lavage fluids. Because FAST(-/-) neutrophils exhibit normal chemotaxis and survival, impaired neutrophil recruitment is likely to be due to reduced production of chemoattractants within the pulmonary parenchyma. Studies using bone marrow chimeras implicate lung resident hematopoietic cells (e.g., pulmonary dendritic cells and/or alveolar macrophages) in this process. In conclusion, our results introduce FAST as a proinflammatory factor that modulates the function of lung resident hematopoietic cells to promote neutrophil recruitment and pulmonary inflammation.

Endogenous estrogens, through estrogen receptor , constrain autoimmune inflammation in female mice by limiting CD4(+) T-cell homing into the CNS

Sex hormones influence immune responses and the development of autoimmune diseases including MS and its animal model, EAE. Although it has been previously reported that ovariectomy could worsen EAE, the mechanisms implicated in the protective action of endogenous ovarian hormones have not been addressed. In this report, we now show that endogenous estrogens limit EAE development and CNS inflammation in adult female mice through estrogen receptor expression in the host non-hematopoietic tissues. We provide evidence that the enhancing effect of gonadectomy on EAE development was due to quantitative rather than qualitative changes in effector Th1 or Th17 cell recruitment into the CNS. Consistent with this observation, adoptive transfer of myelin oligodendrocyte glycoprotein-specific encephalitogenic CD4(+) T lymphocytes induced more severe EAE in ovariectomized mice as compared to normal female mice. Finally, we show that gonadectomy accelerated the early recruitment of inflammatory cells into the CNS upon adoptive transfer of encephalitogenic CD4(+) T cells. Altogether, these data show that endogenous estrogens, through estrogen receptor , exert a protective effect on EAE by limiting the recruitment of blood-derived inflammatory cells into the CNS.

Attenuation of cerebrospinal fluid inflammation by the nonbacteriolytic antibiotic daptomycin versus that by ceftriaxone in experimental pneumococcal meningitis

Antibiotic-induced bacteriolysis exacerbates inflammation and brain damage in bacterial meningitis. Here the quality and temporal kinetics of cerebrospinal fluid (CSF) inflammation were assessed in an infant rat pneumococcal meningitis model for the nonbacteriolytic antibiotic daptomycin versus ceftriaxone. Daptomycin led to lower CSF concentrations of interleukin 1beta (IL-1beta), IL-10, IL-18, monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1 alpha (MIP-1alpha) (P < 0.05). In experimental pneumococcal meningitis, daptomycin treatment resulted in more rapid bacterial killing, lower CSF inflammation, and less brain damage than ceftriaxone treatment.

Inflammation-associated autophagy-related programmed necrotic death of human neutrophils characterized by organelle fusion events

The most common form of neutrophil death, under both physiological and inflammatory conditions, is apoptosis. In this study, we report a novel form of programmed necrotic cell death, associated with cytoplasmic organelle fusion events, that occurs in neutrophils exposed to GM-CSF and other inflammatory cytokines upon ligation of CD44. Strikingly, this type of neutrophil death requires PI3K activation, a signaling event usually involved in cellular survival pathways. In the death pathway reported in this study, PI3K is required for the generation of reactive oxygen species, which somehow trigger the generation of large cytoplasmic vacuoles, generated by the fusion of CD44-containing endosomes with autophagosomes and secondary, but not primary, granules. Neutrophils demonstrating vacuolization undergo rapid cell death that depends on receptor-interacting protein 1 kinase activity and papain family protease(s), but not caspases, that are most likely activated and released, respectively, during or as a consequence of organelle fusion. Vacuolized neutrophils are present in infectious and autoimmune diseases under in vivo conditions. Moreover, isolated neutrophils from such patients are highly sensitive toward CD44-mediated PI3K activation, reactive oxygen species production, and cell death, suggesting that the newly described autophagy-related form of programmed neutrophil necrosis plays an important role in inflammatory responses.

Bifidobacterium lactis attenuates onset of inflammation in a murine model of colitis

To assess the anti-inflammatory effect of the probiotic Bifidobacterium lactis (B. lactis) in an adoptive transfer model of colitis.