51 research outputs found
Activation of activin receptor-like kinases curbs mucosal inflammation and proliferation in chronic rhinosinusitis with nasal polyps
Chronic rhinosinusitis with nasal polyps (CRSwNP) is a widespread disease causing obstruction of the nasal cavity. Its cause remains unclear. The transforming growth-factor beta (TGF-beta) superfamily and their receptors, termed Activin receptor-like kinases (ALKs), have recently been suggested to play a role in local airway inflammation, but have so far not been evaluated in human nasal epithelial cells (HNECs) from CRSwNP patients. We demonstrated that ALK1-7 were expressed in the nasal polyp epithelium, and the expression of ALK1-6 was markedly elevated in polyps compared to nasal mucosa from healthy controls. Stimulation with the ALK ligand TGF-beta 1 decreased Ki67 expression in HNECs from CRSwNP patients, not evident in controls. Likewise, TGF-beta 1, Activin A and Activin B, all ALK ligands, decreased IL-8 release and Activin A and Activin B reduced ICAM1 expression on HNECs from CRSwNP patients, not seen in controls. Pre-stimulation with TGF-beta 1, Activin A, BMP4 and Activin B attenuated a TNF-ainduced ICAM1 upregulation on HNECs of CRSwNP. No effect was evident in controls. In conclusion, an increased expression of ALK1-6 was found on polyp epithelial cells and ligand stimulation appeared to reduce proliferation and local inflammation in polyps
Intranasal Administration of poly(I:C) and LPS in BALB/c Mice Induces Airway Hyperresponsiveness and Inflammation via Different Pathways
BACKGROUND: Bacterial and viral infections are known to promote airway hyperresponsiveness (AHR) in asthmatic patients. The mechanism behind this reaction is poorly understood, but pattern recognizing Toll-like receptors (TLRs) have recently been suggested to play a role. MATERIALS AND METHODS: To explore the relation between infection-induced airway inflammation and the development of AHR, poly(I:C) activating TLR3 and LPS triggering TLR4, were chosen to represent viral and bacterial induced interactions, respectively. Female BALB/c or MyD88-deficient C57BL/6 mice were treated intranasally with either poly(I:C), LPS or PBS (vehicle for the control group), once a day, during 4 consecutive days. RESULTS: When methacholine challenge was performed on day 5, BALB/c mice responded with an increase in airway resistance. The maximal resistance was higher in the poly(I:C) and LPS treated groups than among the controls, indicating development of AHR in response to repeated TLR activation. The proportion of lymphocytes in broncheoalveolar lavage fluid (BALF) increased after poly(I:C) treatment whereas LPS enhanced the amount of neutrophils. A similar cellular pattern was seen in lung tissue. Analysis of 21 inflammatory mediators in BALF revealed that the TLR response was receptor-specific. MyD88-deficient C57BL/6 mice responded to poly (I:C) with an influx of lymphocytes, whereas LPS caused no inflammation. CONCLUSION: In vivo activation of TLR3 and TLR4 in BALB/c mice both caused AHR in conjunction with a local inflammatory reaction. The AHR appeared to be identical regardless of which TLR that was activated, whereas the inflammation exhibited a receptor specific profile in terms of both recruited cells and inflammatory mediators. The inflammatory response caused by LPS appeared to be dependent on MyD88 pathway. Altogether the presented data indicate that the development of AHR and the induction of local inflammation might be the result of two parallel events, rather than one leading to another
Endogenous and exogenous glucocorticoid effects in a model of allergic airway inflammation.
Allergic asthma and rhinitis are inflammatory diseases of the airways.
Allergic asthma is characterized by eosinophilic inflammation, reversible
bronchoconstriction and airway hyperresponsiveness, whereas patients with
rhinitis suffer from nasal inflammation, leading to rhinorrhea and nasal
congestion. Glucocorticoids (GCs) are one of the major drugs for asthma
and rhinitis treatment and can regulate leukocyte trafficking and
mediator release. The hypothalamus pituitary-adrenal (HPA) axis regulates
the secretion of endogenous GCs, and is one of the major stress effector
systems in the body. The main role for the HPA-axis is to facilitate the
maintenance of neuroendocrine homeostasis, both at basal and pathological
conditions. An understanding of the regulation and function of the HPA
axis is important for the evaluation of pathological changes and possible
side effects caused by GCs. In the studies presented in this thesis we
have used a mouse model to investigate the effects of endogenous GC
synthesis and GC receptor inhibition, as well as acute stress, and
different doses of exogenous administered GCs on inflammatory cells in
different cellular compartments in allergic airway inflammation. We also
investigated the effects of acute stress on the neurotrophic mediator,
nerve growth factor (NGF) in the airways, during allergic inflammation.
In the first study (I), we investigated the effects of endogenous GCs on
eosinophilic airway inflammation. Inhibition of GC release with
metyrapone (ME) induced an increase of bone marrow eosinophilia and when
the ME treatment was combined with a GC receptor antagonist (RU 486) the
allergen-induced bone marrow eosinophilia was further enhanced. ME
treatment also induced an increase of CD4+ T lymphocytes in the nasal
mucosa, both when employed as a single treatment and in combination with
RU 486.
In the second study (II), timing and dose-dependent effects of
dexamethasone (DEX) on eosinophilic airway inflammation were studied.
This study provided evidence that a low dose of DEX (1 ”g/kg) evoked a
stronger inhibitory effect on the eosinophilic airway inflammation, as
compared to the effect of the 500 times higher pharmacological dose
(500”g/kg) if given before the allergen challenge. When administered
simultaneously the allergen challenge, the two doses displayed similar
effects.
The third study (III), was focused on the effects of timing of a short
acute stress on allergic airway inflammation in upper and lower airways.
Short stress applied before an allergen challenge decreased the
allergen-induced eosinophilia in bronchoalveolar lavage fluid and lungs
and also the inflammation in the nasal tissue. No effects on eosinophilia
or inflammation were seen when stress was applied after allergen
challenge or as a double stress both before and after challenge. The
protective effects, seen in the mice stressed prior to the allergen
challenge, were GC-dependent.
In the fourth study (IV), the aim was to assess how acute stress
modulated NGF levels and eosinophils in the airways during non-allergic
and mild allergic conditions. We found that short stress increased the
levels of NGF locally in the airways in both allergic and non-allergic
mice. We also demonstrated that airway eosinophils decreased when stress
was applied after allergen-challenge in a model of mild airway
inflammation. The stress-evoked increase in NGF and decrease in
eosinophilia in the airways were dependent on endogenous GC-synthesis, as
evident from pre-treatment with ME.
In summary, these results indicate that endogenous GCs may have a
protective effect in both upper and lower eosinophilic airway
inflammation. Our studies also demonstrate that the inhibitory effect of
GCs on the allergic inflammation is timing-dependent.
By the use of a GC synthesis inhibitor, we show that the inhibitory
effects on the eosinophilic airway inflammation during acute stress are
GC-dependent. Acute stress increased local airway NGF and this effect is
mediated by endogenous GC synthesis. Thus, we also conclude that NGF may
function as a mediator in the psychoneuroimmunological stress-response
Deprived TLR9 expression in apparently healthy nasal mucosa might trigger polyp-growth in chronic rhinosinusitis patients.
The origin of nasal polyps in chronic rhinosinusitis is unknown, but the role of viral infections in polyp growth is clinically well established. Toll-like receptors (TLRs) have recently emerged as key players in our local airway defense against microbes. Among these, TLR9 has gained special interest in viral diseases. Many studies on chronic rhinosinusitis with nasal polyps (CRSwNP) compare polyp tissue with nasal mucosa from polyp-free individuals. Knowledge about changes in the turbinate tissue bordering the polyp tissue is limited.To analyse the role of TLR9 mediated microbial defense in tissue bordering the polyp.Nasal polyps and turbinate tissue from 11 patients with CRSwNP and turbinate tissue from 11 healthy controls in total were used. Five biopsies from either group were analysed immediately with flow cytometry regarding receptor expression and 6 biopsies were used for in vitro stimulation with a TLR9 agonist, CpG. Cytokine release was analysed using Luminex. Eight patients with CRSwNP in total were intranasally challenged with CpG/placebo 24 hours before surgery and the biopsies were collected and analysed as above.TLR9 expression was detected on turbinate epithelial cells from healthy controls and polyp epithelial cells from patients, whereas TLR9 was absent in turbinate epithelial cells from patients. CpG stimulation increased the percentage cells expressing TLR9 and decreased percentage cells expressing VEGFR2 in turbinate tissue from patients. After CpG stimulation the elevated levels of IL-6, G-CSF and MIP-1ÎČ in the turbinate tissue from patients were reduced towards the levels demonstrated in healthy controls.Defects in the TLR9 mediated microbial defense in the mucosa adjacent to the anatomic origin of the polyp might explain virus induced polyp growth. CpG stimulation decreased VEGFR2, suggesting a role for CpG in polyp formation. The focus on turbinate tissue in patients with CRSwNP opens new perspectives in CRSwNP-research
The SPâTLR axis, which locally primes the nasal mucosa, is impeded in patients with allergic rhinitis
Abstract Background Substance P (SP) and tollâlike receptors (TLRs) contribute to airway disease, particularly during viral infection. We recently demonstrated that SP can act as an initial response to viral stimuli in the upper airway by upregulating TLRs in the nasal epithelia (the SPâTLR axis). Patients with allergic rhinitis (AR) suffer from prolonged airway infections. The aim of the present study was to examine if patients with AR exhibit a disturbance in the SPâTLR axis. Method Human nasal biopsies and human nasal epithelial cells (HNEC) from healthy volunteers and patients with AR were cultured in the presence of SP. Epithelial expression of TLR4, neutral endopeptidase (NEP) and neurokinin 1 (NK1) were evaluated with flow cytometry and/or quantitative polymerase chain reaction after 30Â min to 24Â h. The effect of SP on nasal lipopolysaccharideâinduced interleukinâ8 (ILâ8) release was investigated. Results SP stimulation of tissue from healthy volunteers resulted in a transient increase of the TLR4 expression, whereas stimulation of AR patientâderived material led to a delayed and prolonged upregulation of TLR4. NEP expression in HNEC was lower in AR than healthy controls whereas NK1 receptor expression was increased. SP pretreatment increased TLR4âdependent ILâ8 expression in healthy controls, but not in AR. Conclusions SPâinduced regulation of TLR4 in the human nasal mucosa is disturbed in AR. An altered SPâmediated innate immune response may contribute to the dysfunctional and often prolonged responses to infection in AR
LEAP-2, LL-37 and RNase7 in tonsillar tissue: downregulated expression in seasonal allergic rhinitis.
In the upper airway, the production of antimicrobial peptides (AMPs) protects against bacteria, viruses and fungi. Previous investigations have revealed downregulated expression of AMPs in different manifestations of allergic disease. In this study, we examined the expression of LL-37, RNase7 and LEAP-2 in tonsillar tissue and studied a possible relation to seasonal allergic rhinitis (SAR)
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