Hyperreactive Response Research Articles

Airway Hyperreactivity Is Delayed after Mild Neonatal Hyperoxic Exposure

Background: Wheezing disorders are prominent in former preterm infants beyond the neonatal period. Objectives: We used a neonatal mouse model to investigate the time course of airway hyperreactivity in response to mild (40% oxygen) or severe (70% oxygen) neonatal hyperoxia. Methods: After hyperoxic exposure during the first week of postnatal life, we measured changes in airway reactivity using the in vitro living lung slice preparation at the end of exposure [postnatal day 8 (P8)] and 2 weeks later (P21). This was accompanied by measures of smooth muscle actin, myosin light chain (MLC) and alveolar morphology. Results: Neither mild nor severe hyperoxia exposure affected airway reactivity to methacholine at P8 compared to normoxic controls. In contrast, airway reactivity was enhanced at P21 in mice exposed to mild (but not severe) hyperoxia, 2 weeks after exposure ended. This was associated with increased airway α-smooth muscle actin expression at P21 after 40% oxygen exposure without a significant increase in MLC. Alveolar morphology via radial alveolar counts was comparably diminished by both 40 and 70% oxygen at both P8 and P21. Conclusions: These data demonstrate that early mild hyperoxia exposure causes a delayed augmentation of airway reactivity, suggesting a long-term alteration in the trajectory of airway smooth muscle development and consistent with resultant symptomatology.

Aspergillus fumigatus proteases, Asp f 5 and Asp f 13, are essential for airway inflammation and remodelling in a murine inhalation model.

In susceptible individuals, exposure to Aspergillus fumigatus can lead to the development of atopic lung diseases such as allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS). Protease allergens including Asp f 5 and Asp f 13 from Aspergillus fumigatus are thought to be important for initiation and progression of allergic asthma. To assess the importance of secreted protease allergens Asp f 5 (matrix metalloprotease) and Asp f 13 (serine protease) in Aspergillus fumigatus-induced inflammation, airway hyperactivity, atopy and airway wall remodelling in a murine model following chronic exposure to secreted allergens. BALB/c mice were repeatedly intranasally dosed over the course of 5 weeks with culture filtrate from wild-type (WT), Asp f 5 null (∆5) or Asp f 13 null (∆13) strains of Aspergillus fumigatus. Airway hyper-reactivity was measured by non-invasive whole-body plethysmography, Th2 response and airway inflammation by ELISA and cell counts, whilst airway remodelling was assessed by histological analysis. Parent WT and ∆5 culture filtrates showed high protease activity, whilst protease activity in ∆13 culture filtrate was low. Chronic intranasal exposure to the three different filtrates led to comparable airway hyper-reactivity and Th2 response. However, protease allergen deleted strains, in particular ∆13 culture filtrate, induced significantly less airway inflammation and remodelling compared to WT culture filtrate. Aspergillus fumigatus-secreted allergen proteases, Asp f 5 and Asp f 13, are important for recruitment of inflammatory cells and remodelling of the airways in this murine model. However, deletion of a single allergen protease fails to alleviate airway hyper-reactivity and allergic immune response. Targeting protease activity of Aspergillus fumigatus in conditions such as SAFS or ABPA may have beneficial effects in preventing key aspects of airway pathology.

IL-13 mediates IL-33–dependent mast cell and type 2 innate lymphoid cell effects on bronchial epithelial cells

IL-13 mediates IL-33–dependent mast cell and type 2 innate lymphoid cell effects on bronchial epithelial cells

Emotional hyperreactivity in response to childhood abuse by primary caregivers in patients with borderline personality disorder

BackgroundOne of the core postulated features of borderline personality disorder (BPD) is extreme emotional reactivity to a wide array of evocative stimuli. Findings from previous experimental research however are mixed, and some theories suggest specificity of hyper emotional responses, as being related to abuse, rejection and abandonment only. ObjectiveThe current experiment examines the specificity of emotional hyperreactivity in BPD. MethodThe impact of four film clips (BPD-specific: childhood abuse by primary caregivers; BPD-nonspecific: peer bullying; positive; and neutral) on self-reported emotional affect was assessed in three female groups; BPD-patients (n = 24), cluster C personality disorder patients (n = 17) and non-patient controls (n = 23). ResultsResults showed that compared to the neutral film clip, BPD-patients reacted with more overall negative affect following the childhood abuse clip, and with more anger following the peer bullying clip than the two other groups. LimitationsThe current study was restricted to assessment of the impact of evocative stimuli on self-reported emotions, and the order in which the film clips were presented to the participants was fixed. ConclusionsResults suggest that BPD-patients only react generally excessively emotional to stimuli related to childhood abuse by primary caregivers, and with excessive anger to peer-bullying stimuli. These findings are thus not in line with the core idea of general emotional hyperreactvity in BPD.

Rolipram: Eotaxin and phosphodiesterase IV inhibitor versus bronchial hyper-reactivity response.

Sir, I am writing this letter to comment on several previously published articles on the use of phosphodiesterase (PDE) 3 in combination with PDE 4 in patients with bronchial hyper-reactivity.[1,2] These articles suggest the superiority of this combination over conventional treatment; however, as discussed later, rolipram, an investigational PDE 4 inhibitor, may comparatively prove to be more beneficial when used in combination with a beta-agonist and corticosteroids. Bronchial hyper-reactivity responses involve bronchial inflammation characterized by activation and accumulation of dendritic cells, eosinophils, mast cells, macrophages, T-lymphocytes, and tissue remodeling process.[3] Eotaxin, a chemo-attractant, causes up regulation of CD11b, eosinophil accumulation during an allergic response in lungs, and shedding of L-selectin in human eosinophils. Rolipram inhibits CD11b up regulations as well as eotaxin-induced trans-endothelial movement of eosinophils causing inhibition of eosinophil recruitment. In addition, rolipram also inhibit tumor necrosis factor (TNF)-alpha, at both mRNA and protein levels, thus enhancing its anti-inflammatory effects.[4] Moreover, Since PDE 4 enzymes are widely present in the respiratory tract that makes them susceptible to their inhibition by local application therefore inhaled administration of PDE 4 inhibitor has shown considerably more improvement.[5] On the other hand, beta-agonist cause bronchodilation therefore the synergistic effect of beta-agonist with PDE 4 inhibitor is indicated by inhibition of antigen-induced contraction and reduction of increase in vascular permeability which are key factors responsible for the patho-physiology of allergic diseases like asthma.[4] Furthermore, corticosteroids such as dexamethasone and fluticasone also partially reduce the release of eotaxin. The combined use of β2-agonists, rolipram, and steroids abolished TNF-α-induced eotaxin release and hence their combination has additive beneficial effects in the treatment of the eosinophilia associated with asthma and other allergic diseases. Rolipram, being an investigational drug, should be combined with salbutamol and corticosteroids for the management of asthma. In addition, specific eotaxin inhibitors need to be identified that may not only help us to rectify asthmatic problems, but also leads to avoidance of asthmatic exacerbations and most other infections leading to eosinophilia.

Increased risk of tuberculosis in patients with type 1 diabetes mellitus: results from a population-based cohort study in Taiwan.

The studies on the risk of tuberculosis (TB) in patients with type 1 diabetes mellitus (T1DM) alone are limited. We examined this relationship using a population-based retrospective cohort study. From claims data of the National Health Insurance system of Taiwan, we identified 5195 patients with T1DM newly diagnosed from 2002 to 2011 and 20,780 randomly selected controls without T1DM, frequency matched by age, sex, and year of diagnosis. Both cohorts were followed up until the end of 2011 to evaluate the risk of TB. The overall incidence of TB was 4.07-fold higher in the T1DM cohort than in the control cohort (1.18 vs 0.29 per 1000 person-years, P < 0.001). Compared with the controls, the Cox model estimated adjusted hazard ratios (HRs) of TB in patients with T1DM were greater in men than in women (4.62 vs 3.59) and in adults than in children (4.06 vs 3.37), but not significant. The adjusted HR was much greater for those with comorbidities than those without comorbidities (14.6 vs 1.62, P < 0.001). Compared with the controls, the patients with T1DM were also more likely to develop TB with multiple emergency room visits (adjusted HR: 116.1, 95% confidence interval [CI] = 43.8–307.4) or hospitalizations (adjusted HR: 86.5, 95% CI = 33.7–222.4). Patients with T1DM are at elevated risks of developing TB with much higher HRs for those with comorbidities, within the first year of diagnosis, and with frequent emergency cares or hospitalizations.

M13 Laquinimod Reduces Hyper-reactive Pro-inflammatory Cytokine Release From Human Primary Huntington's Disease Myeloid Cells

Background Hyper-reactivity of the innate immune response is an early and active component of Huntington’s disease (HD) and is due in part to NFκB pathway dysregulation. There is evidence that the peripheral immune system plays a disease-modifying role in HD and that targeting it may slow disease progression. Laquinimod (LAQ) is an orally active immunomodulator that has beneficial effects in multiple sclerosis and is thought to act via the NFκB pathway. We investigated whether the compound could also reverse the hyper-reactive immune responses observed in HD. Aims Investigate the effects of LAQ on hyper-reactive HD myeloid cells. Methods Primary human monocytes were isolated from blood collected from symptomatic HD patients, premanifest HD gene-carriers (PreHD) and healthy volunteers. Cells were pretreated with 1μM or 5μM LAQ for 2 or 24 hours (h) before being stimulated with LPS for 24h. Cytokine release was measured by ELISA. IκB degradation kinetics, nuclear translocation of NFκB, and interactions between IKK and HTT were assessed in LAQ-treated cells. Results Twenty-four hour pretreatment with 5μM LAQ reduced cytokine release in manifest HD patient monocytes. This included IL-1β, IL-8, TNFα, IL-5, IL-13 and IL-10. Reductions in IL-6, IL-8, IL-10 and IL-13 release by preHD monocytes were also observed using this LAQ dose. When using either 1µM LAQ or 2h pretreatment there was little evidence of a difference between active and control conditions in any of the patient subgroups. We did not observe any significant effect of LAQ on IκB degradation kinetics, NFκB translocation or interactions between IKK and HTT. Conclusions 5μM LAQ applied to HD monocytes for 24h reduces hyper-reactive cytokine production in response to LPS stimulation. The mechanism for this does not appear to be downstream of NFκB activation. We are currently working on elucidating the mechanism of action of LAQ and will go on to determine how this impacts on neuronal survival using neuronal-myeloid cell co-culture models.

Population of sensory neurons essential for asthmatic hyperreactivity of inflamed airways.

Asthma is a common debilitating inflammatory lung disease affecting over 200 million people worldwide. Here, we investigated neurogenic components involved in asthmatic-like attacks using the ovalbumin-sensitized murine model of the disease, and identified a specific population of neurons that are required for airway hyperreactivity. We show that ablating or genetically silencing these neurons abolished the hyperreactive broncho-constrictions, even in the presence of a fully developed lung inflammatory immune response. These neurons are found in the vagal ganglia and are characterized by the expression of the transient receptor potential vanilloid 1 (TRPV1) ion channel. However, the TRPV1 channel itself is not required for the asthmatic-like hyperreactive airway response. We also demonstrate that optogenetic stimulation of this population of TRP-expressing cells with channelrhodopsin dramatically exacerbates airway hyperreactivity of inflamed airways. Notably, these cells express the sphingosine-1-phosphate receptor 3 (S1PR3), and stimulation with a S1PR3 agonist efficiently induced broncho-constrictions, even in the absence of ovalbumin sensitization and inflammation. Our results show that the airway hyperreactivity phenotype can be physiologically dissociated from the immune component, and provide a platform for devising therapeutic approaches to asthma that target these pathways separately.

Awake thoracic epidural anaesthesia for laparotomy: A safer alternative to general anaesthesia in asthmatic patients

Asthma is a common obstructive lung disease with a hallmark of airway inflammation and hyper-reactivity in response to a variety of stimuli. The morbidity and mortality in asthma is directly related to reversible airway obstruction and bronchospasm in response to specific triggers. The goal of the anaesthetist is to avoid eliciting triggering stimuli that can incite bronchospasm. Neuromuscular blocking agents and invasive airway procedures like endotracheal intubation are known triggering factors for bronchospasm in asthmatics. It is therefore prudent to use regional, as oppose to general, anaesthesia whenever possible. We describe the use of an awake thoracic epidural anaesthesia for laparotomy in an asthmatic patient. We recommend that, where possible, epidural anaesthesia should be preferred to general anaesthesia in asthmatic patients.

Age-associated alterations in the time-dependent profile of pro- and anti-inflammatory proteins within the hippocampus in response to acute exposure to interleukin-1β

The pro-inflammatory cytokine IL-1β is known to play a role in several models of aging, neuroinflammation, and neurodegenerative diseases. Here, we document a detailed time- and age-dependent pattern of pro- and anti-inflammatory biomarkers following bilateral intrahippocampal injection of interleukin-1β. During the first 12h several pro- and anti-inflammatory cytokines increased in the aged (24mo old) rats, some of which returned to baseline levels by 24h post-injection while others remained elevated for 72h post-injection. In contrast, no such increases were observed in the young (3mo old) rats. Interestingly, young rats up-regulated mRNA of two pro-inflammatory cytokines, interleukin-1β and tumor necrosis factor-α, but did not translate these transcripts into functional proteins, which may be related to expression of suppressor of cytokine signaling type-2. These results contribute to our understanding of how neuroinflammation may contribute to the pathogenesis of age-related neurodegenerative disorders due to an age-related bias towards a hyper-reactive immune response that is not selective for a pro- or anti-inflammatory phenotype following an inflammatory stimulus.

Épisodes dépressifs mixtes : clinique et biomarqueurs neurophysiologiques

Epidemiological studies of major depressive episodes (MDE) highlighted the frequent association of symptoms or signs of mania or hypomania with depressive syndrome. Beyond the strict definition of DSM-IV, epidemiological recognition of a subset of MDE characterized by the presence of symptoms or signs of the opposite polarity is clinically important because it is associated with pejorative prognosis and therapeutic response compared to the subgroup of "typical MDE". The development of DSM-5 took into account the epidemiological data. DSM-5 opted for a more dimensional perspective in implementing the concept of "mixed features" from an "episode" to a "specification" of mood disorder. As outlined in the DSM-5: "Mixed features associated with a major depressive episode have been found to be a significant risk factor for the development of bipolar I and II disorder. As a result, it is clinically useful to note the presence of this specifier for treatment planning and monitoring of response to therapeutic". However, the mixed features are sometimes difficult to identify, and neurophysiological biomarkers would be useful to make a more specific diagnosis. Two neurophysiological models make it possible to better understand MDE with mixed features : i) the emotional regulation model that highlights a tendency to hyper-reactive and unstable emotion response, and ii) the vigilance regulation model that highlights, through EEG recording, a tendency to unstable vigilance. Further research is required to better understand relationships between these two models. These models provide the opportunity of a neurophysiological framework to better understand the mixed features associated with MDE and to identify potential neurophysiological biomarkers to guide therapeutic strategies.

Host-pathogen interactions in tuberculosis patients with type 2 diabetes mellitus

Tuberculosis (TB) is known to be fueled by HIV as well as social and economic factors. With progression of the diabetes mellitus (DM) pandemic in countries where TB is also endemic, focus is increasing on the potential links between DM and TB. Despite the magnitude of the DM-TB association woldwide, it is striking how little we know about the underlying biology that promotes this association which is a major concern to public health. In this review we summarize current findings regarding the alterations in the innate and adaptive immune responses of DM patients to Mycobacterium tuberculosis (Mtb). Current findings suggest underperforming innate immunity followed by a hyper-reactive cellular response to Mtb, but the contribution of these altered responses to TB susceptibility or to the more adverse clinical outcomes of TB patients with DM remains unclear. Elucidating the basic mechanisms underlying the higher susceptibility of DM patients to TB should lead to a strategy for stratification of the millions of DM patients worldwide into those with the highest TB risk for targeted TB prevention.

Requirement of Apoptosis-Inducing Kinase 1 for the Induction of Bronchial Asthma following Stimulation with Ovalbumin

Background: Bronchial asthma is a chronic inflammatory disease of the airway. Apoptosis signal-regulating kinase 1 (ASK1), a member of the mitogen-activated protein kinase kinase kinase family, is activated by environmental stress and plays a crucial role in the induction of apoptosis and inflammation. To examine whether ASK1 is involved in the induction of bronchial asthma, we investigated the role of ASK1 using a genetic approach in the production of cytokines, as well as the development of airway hyperreactivity (AHR) and antibody responses using a murine airway inflammation model. Methods: ASK1-deficient (ASK1^-/-) and control wild-type (WT) mice were immunized with ovalbumin (OVA) without alum intraperitoneally, followed by intranasal administration of OVA. Airway infiltration of inflammatory cells, cytokine production, AHR and antibody production were assayed. The asthmatic phenotype was assessed following intranasal administration of IL-13 or TNF-α. Results: ASK1^-/- mice sensitized with OVA displayed an impaired inflammatory cell infiltration into airways and a decreased AHR relative to WT mice. Moreover, the production of OVA-specific IgE antibodies and proasthmatic cytokines (IL-5, IL-13 and TNF-α) was substantially reduced in OVA-stimulated ASK1^-/- mice. Intranasal administration of IL-13 and OVA enhanced the accumulation of inflammatory cells in OVA-primed ASK1^-/- mice. The OVA-induced AHR in response to methacholine was enhanced by IL-13 in WT mice but not ASK1^-/- mice. Conclusions: The ASK1 signaling pathway regulates the OVA-induced asthmatic phenotype, specifically AHR sensitivity and cytokine production. Therefore, the ASK1 signaling pathway is a promising target for therapeutic intervention in some asthmatic patients.

Comparison of ultraviolet B-induced cutaneous inflammation and skin pathergy test in Behçet’s disease

Background: Nonspecific hyper-reactive inflammatory response is an important feature of Behcet’s disease (BD), but the underlying mechanism has yet to be identified. Ultraviolet B (UVB)-induced erythema is a well-established experimental method for the investigation of antigen-independent cutaneous inflammation, and no data are available on UVB response in BD patients. Aim: To investigate the UVB-induced erythema by determining the minimal erythema dose in BD patients and matched healthy controls, and also to compare the results of UVB response with the skin pathergy reaction. Patients & methods: The study group consisted of 47 patients with BD, 32 with various rheumatic diseases and 21 healthy volunteers. UVM-57 (Ultraviolet Products, Cambridge, UK; 302 nm), was used as the narrow-band UVB source. The forearm of each individual was exposed to a 0.14–10.45 J/cm2 dose of 302-nm UVB with 0.045 J/cm2 increments. The skin pathergy reaction was tested using a 20 G hypodermic needle as previously described. The...

Macrophage TNF-α mediates parathion-induced airway hyperreactivity in guinea pigs.

Organophosphorus pesticides (OPs) are implicated in human asthma. We previously demonstrated that, at concentrations that do not inhibit acetylcholinesterase activity, the OP parathion causes airway hyperreactivity in guinea pigs as a result of functional loss of inhibitory M2 muscarinic receptors on parasympathetic nerves. Because macrophages are associated with asthma, we investigated whether macrophages mediate parathion-induced M2 receptor dysfunction and airway hyperreactivity. Airway physiology was measured in guinea pigs 24 h after a subcutaneous injection of parathion. Pretreatment with liposome-encapsulated clodronate induced alveolar macrophage apoptosis and prevented parathion-induced airway hyperreactivity in response to electrical stimulation of the vagus nerves. As determined by qPCR, TNF-α and IL-1β mRNA levels were increased in alveolar macrophages isolated from parathion-treated guinea pigs. Parathion treatment of alveolar macrophages ex vivo did not significantly increase IL-1β and TNF-α mRNA but did significantly increase TNF-α protein release. Consistent with these data, pretreatment with the TNF-α inhibitor etanercept but not the IL-1β receptor inhibitor anakinra prevented parathion-induced airway hyperreactivity and protected M2 receptor function. These data suggest a novel mechanism of OP-induced airway hyperreactivity in which low-level parathion activates macrophages to release TNF-α-causing M2 receptor dysfunction and airway hyperreactivity. These observations have important implications regarding therapeutic approaches for treating respiratory disease associated with OP exposures.

Tumor necrosis factor-α production by blood mononuclear cells in different manifestations of sarcoidosis

Summary. Tumor necrosis factor-α (TNF-α) is a polypeptide mediator and proinflammatory cytokine that plays an important role for pathogenesis of sarcoidosis. The aim of this study was to investigate spontaneous and induced by M.bovis antigen (BCG) and mitogen concanavalin (Con A) production of TNF-α by peripheral blood mononuclear cells in patients with different manifestations of sarcoidosis. The study involved 22 patients with active sarcoidosis of intrathoracic lymph nodes and lungs. TNF-α production was studied in supernatants of blood mononuclear cell cultures using sandwich method and immunoenzyme analysis (ELISE). We found a significant increase in spontaneous and induced TNF-α production in patients with acute sarcoidosis compared to asymptomatic patients and with healthy volunteers. TNF-α hyperproduction induced by non-specific mitogen Con A was also revealed in all sarcoidosis patients regardless of activity of the disease in comparison with healthy controls. These data may indicate an increased functional activity of the immune cells and their tendency to hyperreactivity in response to antigen in patients with sarcoidosis.

Airway epithelium is a predominant source of endogenous airway GABA and contributes to relaxation of airway smooth muscle tone

Chronic obstructive pulmonary disease and asthma are characterized by hyperreactive airway responses that predispose patients to episodes of acute airway constriction. Recent studies suggest a complex paradigm of GABAergic signaling in airways that involves GABA-mediated relaxation of airway smooth muscle. However, the cellular source of airway GABA and mechanisms regulating its release remain unknown. We questioned whether epithelium is a major source of GABA in the airway and whether the absence of epithelium-derived GABA contributes to greater airway smooth muscle force. Messenger RNA encoding glutamic acid decarboxylase (GAD) 65/67 was quantitatively measured in human airway epithelium and smooth muscle. HPLC quantified GABA levels in guinea pig tracheal ring segments under basal or stimulated conditions with or without epithelium. The role of endogenous GABA in the maintenance of an acetylcholine contraction in human airway and guinea pig airway smooth muscle was assessed in organ baths. A 37.5-fold greater amount of mRNA encoding GAD 67 was detected in human epithelium vs. airway smooth muscle cells. HPLC confirmed that guinea pig airways with intact epithelium have a higher constitutive elution of GABA under basal or KCl-depolarized conditions compared with epithelium-denuded airway rings. Inhibition of GABA transporters significantly suppressed KCl-mediated release of GABA from epithelium-intact airways, but tetrodotoxin was without effect. The presence of intact epithelium had a significant GABAergic-mediated prorelaxant effect on the maintenance of contractile tone. Airway epithelium is a predominant cellular source of endogenous GABA in the airway and contributes significant prorelaxant GABA effects on airway smooth muscle force.

HEPATIC STEATOSIS IS INDEPENDENTLY ASSOCIATED WITH HYPERREACTIVE BLOOD PRESSURE RESPONSE ON THE EXERCISE STRESS TEST

Background: Hepatic steatosis (HS) is associated with insulin resistance, the metabolic syndrome, subclinical inlammation and a higher risk of cardiovascular disease. Blood pressure hyperreactivity during peak exercise is associated with an increased risk of developing hypertension and with increased cardiovascular risk. Clinical predictors of hyperreactive response (HRR) are not well established. We studied the association between hepatic steatosis (HS) and HRR.

Isometric responses of isolated intrapulmonary bronchioles from cats with and without adult heartworm infection

To determine the isometric responses of isolated intrapulmonary bronchioles from cats with and without adult heartworm infection. 13 purpose-bred adult cats. Cats were infected with 100 third-stage larvae or received a sham inoculation, and the left caudal lung lobe was collected 278 to 299 days after infection. Isometric responses of intrapulmonary bronchiolar rings were studied by use of a wire myograph. Three cycles of contractions induced by administration of 10 μM acetylcholine were followed by administration of the contractile agonists acetylcholine, histamine, and 5-hydroxy-tryptamine. To evaluate relaxation, intrapulmonary bronchiolar rings were constricted by administration of 10 μM 5-hydroxytryptamine, and concentration-response curves were generated from administration of sodium nitroprusside, isoproterenol, and substance P. Compared with tissues from control cats, contractile responses to acetylcholine and 5-hydroxytryptamine were reduced in tissues from heartworm-infected cats. Relaxation to isoproterenol was significantly reduced in tissues from heartworm-infected cats. Relaxation to substance P was increased in tissues from heartworm-infected cats, but relaxation to sodium nitroprusside was unchanged. Results suggested that despite increased bronchiolar wall thickness in heartworm-infected cats, a hyperreactive response of the bronchiolar smooth muscle is not the primary mechanism of respiratory tract clinical signs. Reduced response of the airway to isoproterenol may indicate refractoriness to bronchiolar relaxation in heartworm-infected cats.

Attenuation of airway hyperreactivity and T helper cell type 2 responses by coumarins from Peucedanum praeruptorum Dunn in a murine model of allergic airway inflammation

Ethnopharmacological relevanceThe root of Peucedanum praeruptorum Dunn (PPD) is a commonly used traditional Chinese medicine for the treatment of asthma. Its major constituents, coumarins, were presumed to be responsible for its efficacy. Aim of the studyThe potential of coumarins from PPD (CPPD) as anti-asthma agent was investigated. Materials and methodsFemale BALB/c mice were sensitized and challenged with ovalbumin (OVA) to induce allergic airway inflammation. CPPD was administered intragastrically before every OVA challenge. Airway reactivity to the intravenous administration of acetylcholine chloride was measured 48h after final OVA inhalation. Airway inflammation was evaluated by leukocyte counts of bronchoalveolar lavage fluid (BALF) and histopathological analysis of lung lesions. Levels of interleukin (IL)-4, IL-5, IL-10, IL-13 and IFN-γ in BALF and OVA-specific immunoglobulin (Ig) E in serum, and activity of eosinophil peroxidase (EPO) in lung was measured. The percentage of CD4+CD25+Foxp3+ regulatory T cells among CD4+ T cells in spleen was analyzed by flow cytometry. ResultsCompared with model group, CPPD significantly reduced airway hyperreactivity and airway eosinophilic inflammation, improved pathologic lesion of the lungs, reduced levels of IL-4, IL-5, IL-13 in BALF and OVA-specific IgE in serum, inhibited the activities of EPO in lung, and up-regulated levels of IL-10 and IFN-γ in BALF as well as the percentage of CD4+CD25+Foxp3+ regulatory T cells in spleen. ConclusionCPPD can significantly suppress OVA-induced airway inflammation, airway hyperreactivity and Th2 predominant response in mice, showing great therapeutic potential for the treatment of allergic asthma.