284 research outputs found
Heterogeneity of mononuclear phagocytes in interstitial lung diseases
Interstitial lung diseases are a heterogeneous group of illnesses with different
pathogeneses. In interstitial lung diseases there often is an increased influx of cells from the
peripheral blood (PB) to the interstitium and alveoli. Besides the increase in total cell numbers,
often marked shifts in the cell populations occur.
This thesis describes the immunophenotype of the cells involved in three types of interstitial
lung diseases, namely sarcoidosis, idiopathic pulmonary fibrosis (IPF) and extrinsic allergic
alveolitis (EM). Emphasis is put on monocytic cells and macrophages. The cell surface
markers of monocytes and macrophages as well as the immunophenotype of cultured purified
monocytes have been studied. In addition surface antigens of cells from PB and
bronchoalveolar lavage (BAL) fluid have been studied in the forementioned interstitial lung
disease
Cyclic AMP enhancing drugs modulate eicosanoid release from human alveolar macrophages
The effect of the phosphodiesterase inhibitor isobutyl-methylxanthine (IBMX), salbutamol and sodium nitroprusside was evaluated regarding PGE2 and LTB4 release and cAMP and cGMP level in human alveolar macrophages obtained from controls and COPD patients. Basal levels per five million control-respectively COPD alveolar macrophages: cAMP 1.2 and 1.0 pmole; cGMP 8.4 and 9.1 fmole; PGE2 120 and 63 pg and LTB4 19.2 and 14.8 pg. In both populations IBMX increased cAMP level by 55–93% and salbutamol+IBMX by 285-252%. Except for the 61% rise in LTB4 release by salbutamol+IBMX the drugs hardly affected PGE2 and LTB4 release from control macrophages. In COPD alveolar macrophages, however, IBMX and IBMX+salbutamol largely reduced PGE2 release (63 vs 11 pg per 106 cells) but less efficiently increased LTB4. In both macrophage populations sodium nitroprusside (SNP) substantially increased (3–4 fold) cGMP level but did not affect eicosanoid production. Present results indicate that drugs which enhance cAMP level decrease PGE2 release from COPD macrophages and stimulate the release of LTB4 a chemotactic mediator involved in bronchial inflammatory reactions
Lung dendritic cells and host immunity to infection
The lung is a portal of entry for numerous microbial pathogens, against
which evolution has created an adequate innate and adaptive immune
response. Dendritic cells (DCs) are central to the integration of innate
and specific immunity. These cells are located within the epithelium and
interstitium of the lung where they are influenced by the innate immune
system. Upon recognition and internalization of microbial antigens, DCs
migrate to the draining lymph nodes of the lung to initiate the specific
cellular and humoral immune response. By their capacity to integrate
stimuli derived from the pathogen, the host and the environment, they are
specialized to induce a protective immune response while at the same time
avoiding damage to the host. It is becoming increasingly clear that
dendritic cells are involved in the induction of immunity to viruses,
bacteria, mycobacteria and fungi. Some pathogens subvert the function of
dendritic cells to escape immune recognition. Not surprisingly, if
dendritic cell function fails, the consequence for the host is
immunodeficiency
Eosinophils in the bronchial mucosa in relation to methacholine dose-response curves in atopic asthma
Asthma is characterized by both local infiltration of eosinophils in the
bronchial mucosa and bronchial hyperreactivity (BHR). A detailed
characterization of BHR implies analysis of a histamine or methacholine
dose-response curve yielding not only the dose at 20% fall of baseline
forced expiratory volume in 1 s (FEV1), but also a plateau (P)
representing the maximal narrowing response in terms of percent change in
FEV1 and reactivity as the steepest slope at 50% of P (%FEV1/doubling
dose). In the baseline condition, the specific airway conductance (sGaw)
may be considered closely related to airway lumen diameter. In 20
nonsmoking asthmatic patients, methacholine dose-response curves were
obtained, and a sigmoid model fit yielded the BHR indexes.
Immunohistochemistry with the monoclonal antibodies (EG1 and EG2) was used
to recognize the total number of eosinophils and activated eosinophils,
respectively. The number of activated eosinophils was significantly
correlated to both P (r = 0.62; P < 0.05) and sGaw (r = -0.52; P < 0.05),
whereas weaker and nonsignificant correlations were found for dose at 20%
fall of baseline FEV1 and the total number of eosinophils. We conclude
that the number of activated eosinophils can be considered a marker of the
inflammation-induced decrease of airway lumen diameter as represented by
the plateau index and sGaw
Activation of the D prostanoid 1 receptor suppresses asthma by modulation of lung dendritic cell function and induction of regulatory T cells
Prostaglandins (PGs) can enhance or suppress inflammation by acting on different receptors expressed by hematopoietic and nonhematopoietic cells. Prostaglandin D2 binds to the D prostanoid (DP)1 and DP2 receptor and is seen as a critical mediator of asthma causing vasodilation, bronchoconstriction, and inflammatory cell influx. Here we show that inhalation of a selective DP1 agonist suppresses the cardinal features of asthma by targeting the function of lung dendritic cells (DCs). In mice treated with DP1 agonist or receiving DP1 agonist-treated DCs, there was an increase in Foxp3+ CD4+ regulatory T cells that suppressed inflammation in an interleukin 10–dependent way. These effects of DP1 agonist on DCs were mediated by cyclic AMP–dependent protein kinase A. We furthermore show that activation of DP1 by an endogenous ligand inhibits airway inflammation as chimeric mice with selective hematopoietic loss of DP1 had strongly enhanced airway inflammation and antigen-pulsed DCs lacking DP1 were better at inducing airway T helper 2 responses in the lung. Triggering DP1 on DCs is an important mechanism to induce regulatory T cells and to control the extent of airway inflammation. This pathway could be exploited to design novel treatments for asthma
Prostaglandin D2 inhibits airway dendritic cell migration and function in steady state conditions by selective activation of the D prostanoid receptor 1
PGD(2) is the major mediator released by mast cells during allergic
responses, and it acts through two different receptors, the D prostanoid
receptor 1 (DP1) and DP2, also known as CRTH2. Recently, it has been shown
that PGD(2) inhibits the migration of epidermal Langerhans cells to the
skin draining lymph nodes (LNs) and affects the subsequent cutaneous
inflammatory reaction. However, the role of PGD(2) in the pulmonary immune
response remains unclear. Here, we show that the intratracheal
instillation of FITC-OVA together with PGD(2) inhibits the migration of
FITC(+) lung DC to draining LNs. This process is mimicked by the DP1
agonist BW245C, but not by the DP2 agonist DK-PGD(2). The ligation of DP1
inhibits the migration of FITC-OVA(+) DCs only temporarily, but still
inhibits the proliferation of adoptively transferred, OVA-specific,
CFSE-labeled, naive T cells in draining LNs. These T cells produced lower
amounts of the T cell cytokines IL-4, IL-10, and IFN-gamma compared with T
cells from mice that received FITC-OVA alone. Taken together, our data
suggest that the activation of DP receptor by PGD(2) may represent a
pathway to control airway DC migration and to limit the activation of T
cells in the LNs under steady state conditions, possibly contributing to
homeostasis in th
Effects of fluticasone propionate on methacholine dose-response curves in nonsmoking atopic asthmatics
Methacholine is frequently used to determine bronchial hyperresponsiveness
(BHR) and to generate dose-response curves. These curves are characterized
by a threshold (provocative concentration of methacholine producing a 20%
fall in forced expiratory volume in one second (PC20) = sensitivity),
slope (reactivity) and maximal response (plateau). We investigated the
efficacy of 12 weeks of treatment with 1,000 microg fluticasone propionate
in a double-blind, placebo-controlled study in 33 atopic asthmatics. The
outcome measures used were the influence on BHR and the different indices
of the methacholine dose-response (MDR) curve. After 2 weeks run-in,
baseline lung function data were obtained and a MDR curve was measured
with doubling concentrations of the methacholine from 0.03 to 256 mg x
mL(-1). MDR curves were repeated after 6 and 12 weeks. A recently
developed, sigmoid cumulative Gaussian distribution function was fitted to
the data. Although sensitivity was obtained by linear interpolation of two
successive log2 concentrations, reactivity, plateau and the effective
concentration at 50% of the plateau value (EC50) were obtained as best fit
parameters. In the fluticasone group, significant changes occurred after 6
weeks with respect to means of PC20 (an increase of 3.4 doubling doses),
plateau value fall in forced expiratory volume in one second (FEV1) (from
58% at randomization to 41% at 6 weeks) and baseline FEV1 (from 3.46 to
3.75 L) in contrast to the placebo group. Stabilization occurred after 12
weeks. Changes for reactivity were less marked, whereas changes in log,
EC50 were not significantly different between the groups. We conclude that
fluticasone is very effective in decreasing the maximal airway narrowing
response and in increasing PC20. However, it is likely that part of this
increase is related to the decrease of the plateau of maximal response
The influence of the diagnostic technique on the histopathological diagnosis in malignant mesothelioma
In the histopathology of malignant mesotheliomas three different types (epithelial, connective tissue and mixed type) are distinguished. Some authors believe all tumours to be of mixed type, but consider that due to inadequate sampling or small biopsies this may be missed frequently. In this study the relationship between the histopathological diagnosis and the amount of tissue examined was investigated. In a series of 124 cases of malignant pleural mesothelioma a high percentage of mixed type tumours was found (55%). In cases where the decisive diagnostic procedure had been an Abrams biopsy (the "small-specimen" technique) mixed-type histology was found in 36%. If thoracoscopy, thoracotomy or autopsy (the "large-specimen" techniques) had delivered a definite diagnosis, mixed-type histology was found in 63%. Apparently diagnosing the mixed-type variety depends on the amount of tumour tissue obtained. However, the assumption that all mesotheliomas are of mixed type cannot be confirmed
Adolescents in clinical remission of atopic asthma have elevated exhaled nitric oxide levels and bronchial hyperresponsiveness
Symptoms of atopic asthma often decrease or even seem to disappear around
puberty. The aim of this study was to investigate whether this so-called
clinical remission is accompanied by remission of airway inflammation,
since symptoms relapse in a substantial proportion of subjects later in
life. To assess indicators of inflammation and/or structural damage of the
airways, exhaled nitric oxide (eNO) and bronchial responsiveness to
adenosine-5'-monophosphate (AMP) and methacholine (MCh) were determined in
21 subjects in clinical remission of atopic asthma. Clinical remission was
defined as complete absence of symptoms of asthma without the use of any
medication in the year preceding the study. Results were compared with
those of 21 patients with current asthma and 18 healthy control subjects.
We found significantly higher eNO values in the remission group than in
healthy controls (geometric mean, 18.9 and 1.0 ppb, respectively; p <
0.001) whereas eNO values of the remission group and those of the subjects
with current asthma (geometric mean, 21.9 ppb) were similar (p = 0.09).
The responsiveness to both AMP and MCh of subjects in clinical remission
was significantly higher as compared with responsiveness of healthy
controls, and lower than responsiveness of subjects with current asthma. A
significant correlation could be established between eNO and
responsiveness to AMP, but not between eNO and responsiveness to MCh. The
results of this study are suggestive of persistent airway inflammation
during clinical remission of atopic asthma. We speculate that subclinical
inflammation is a risk factor for asthma relapse later in life, and that
eNO and responsiveness to both AMP and MCh can be used as different,
noninvasive indices of the inflammatory process of the airways
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