Airway inflammation: chemokine-induced neutrophilia and the class I phosphoinositide 3-kinases

Class I phosphoinositide 3-kinases (PI3K) are known to play a significant role in neutrophil chemotaxis. However, the relative contributions of different PI3K isoforms, and how these impact on lung inflammation, have not been addressed. In vitro studies using wild-type and PI3Kgamma knockout neutrophils demonstrated the major role of the gamma isoform in chemotactic but not chemokinetic events. This was confirmed by a model of direct chemokine instillation into the airways in vivo. Within all studies, a low yet significant degree of neutrophil movement in the absence of PI3Kgamma could be observed. No role for the delta isoform was demonstrated both in vitro and in vivo using PI3Kdelta kinase-dead knock-in mice. Moreover, further studies using the broad-spectrum PI3K inhibitors wortmannin or LY294002 showed no other class I PI3K isoforms to be involved in these chemotactic processes. Here, we identify a contributory PI3K-independent mechanism of neutrophil movement, yet demonstrate PI3Kgamma as the pivotal mediator through which the majority of neutrophils migrate into the lung in response to chemokines. These data resolve the complexities of chemokine-induced neutrophilia and PI3K signaling and define the gamma isoform as a promising target for new therapeutics to treat airway inflammatory diseases.     

慢性支气管炎、肺气肿时肺动脉高压与肺血管壁改建与炎症的关系

目的：研究慢性支气管炎(慢支)、肺气肿气道及肺部炎症在肺动脉重塑中的作用。方法:24只雄性Wistar大鼠分3组，每组8只；慢支、肺气肿4周组（A组）、慢支、肺气肿6周组（B组）、正常对照组（C组）。气管内注入脂多糖（LPS）和每天烟熏的混合刺激方法制作慢支、肺气肿动物模型。测定各组血气分析、肺血流动力学和肺泡灌洗液(BALF)细胞分类计数；观测气道、肺泡组织及肺血管的病理组织学改变。结果:（1）A、B组BALF细胞总数显著高于C组，细胞分类及气道壁浸润的细胞中，A组以中性粒细胞为主，B组以淋巴细胞、单核巨噬细胞为主，其气管、支气管及肺组织具有慢支、肺气肿的病理特征。（2）A、B组右心室收缩压（RVSP）、平均肺动脉压（mPAP）、右心室与左心室＋室间隔重量比（RV/LV+S）高于C组（P<0.05）。A、B肌化型动脉（MA）数量比亦高于C组(P<0.05)。（3）A、B组MA百分比、mPAP与平均肺泡面积,BALF细胞总数和中性粒细胞、淋巴细胞、单核巨噬细胞对小气道浸润程度呈正相关，与PaO2无相关性。在A组中，MA百分比、mPAP与BALF细胞数的中性粒细胞百分比呈正相关，而在B组中，与淋巴细胞百分比、单核巨噬细胞百分比呈正相关 。结论：（1）慢支、肺气肿在无低氧血症时已出现肺动脉高压、右心室肥厚及肺动脉重塑，其发生机制与气道及肺部的炎症浸润及炎症破坏程度相关。（2）此阶段肺动脉重塑改变以肺小动脉肌化为主要特点，并与肺血流动力学改变呈正相关。     

Inflammation in lung transplantation for CF. Immunosuppression and modulation of inflammation

Lung transplantation is an accepted therapy for selected individuals with end-stage lung disease due to cystic fibrosis (CF). Recent data show that CF recipients oflung transplantation have survival as good as those of any other diagnostic group. After transplantation, CF patients confront the major threats to life and health of graft infection and rejection. Inflammation is the common mediator of injury to the lung in both these instances. Graft infection after lung transplantation involves the same micro-organismsas are typical with CF as well as opportunistic agents. Prophylactic strategies and aggressive diagnosis via bronchoscopy are both critical in the effective treatment of post-transplant lung infections. Graft rejection involves the detection and recognition of foreign antigen and the subsequent activation of specific T-lymphocyte clones leading to inflammatory injury to the donor organ. Immunosuppression is used to prevent and/or modulate host response to the donor organ and titrated to serum therapeutic drug monitoring and transbronchial biopsy findings. Precise clinical monitoring and aggressive diagnostic approaches are crucial to minimizing graft injury and aggressive diagnostic approaches are crucial to minimizing graft injury and enhancing life after transplantation. Although most CF lung transplant recipients experience both graft infection and rejection and the 5-yr survival rate remains at approx 50%, improvement in diagnosis and therapy continue over time. With the introduction of new approaches to antimicrobial therapy, new immunosuppressant agents and promising strategies to promote immune tolerance, survival after lung transplantation is likely to improve in the coming decades.     

Comparison of Clinical and Radiographic Characteristics between Nodular Bronchiectatic Form of Nontuberculous Mycobacterial Lung Disease and Diffuse Panbronchiolitis

The nodular bronchiectatic form of nontuberculous mycobacterial (NTM) lung disease and diffuse panbronchiolits (DPB) show similar clinical and radiographic findings. The present study was performed to clarify the clinicoradiographic similarities as well as the differences between NTM lung disease and DPB. The initial clinicoradiographic features of 78 patients with the nodular bronchiectatic form of NTM lung disease (41 patients with Mycobacterium avium complex infection and 37 patients with Mycobacterium abscessus infection) were compared with those of 35 patients with DPB. Old age, female sex, a history of tuberculosis treatment, and hemoptysis were related to NTM lung disease while exertional dyspnea, coarse crackles, history of sinusitis, obstructive abnormalities in pulmonary function tests, and hypoxemia were related to DPB. The number of lobes involved with bronchiolitis and bronchiectasis on chest computed tomography were more numerous in DPB patients. There is considerable overlap in the clinical and radiographic appearances of the nodular bronchiectatic form of NTM lung disease and DPB, although some clinicoradiographic features differ between two diseases. The correct diagnosis, including aggressive microbiologic evaluation, should be made for the appropriate management of patients presenting with bilateral bronchiectasis and bronchiolitis.     

多层螺旋CT三维成像行国人气道径线分析

目的探讨国人气管和主支气管各种解剖径线的长度与角度.方法用多层螺旋CT三维成像法测定300例成年健康体检者锁骨胸骨端水平气管内径、锁骨胸骨端水平到隆突的气管长度,左、右主支气管和右中间支气管内径与长度,以及左、右主支气管长轴与矢状面的夹角.结果男性气管、左、右主支气管、右中间支气管内径与长度,以及右上肺叶支气管开口内径均大于女性,而女性左、右主支气管长轴与矢状面夹角均大于男性(p<0.05或0.01).成年人与老年人上述各解剖径线值差异无显著(p>0.05).左主支气管内径值与右主支气管内径值呈高度相关,且分别与气管内径值和身高呈高度相关(p<0.01).结论通过多层螺旋CT三维成像法测定国人气管、左和右主支气管径线值,获左、右主支气管内径值与患者身高和气管内径测量值的回归方程,可预测其左、右主支气管内径值.     

Airway disease: similarities and differences between asthma, COPD and bronchiectasis

Airway diseases are highly prevalent worldwide; however, the prevalence of these diseases is underestimated. Although these diseases present several common characteristics, they have different clinical outcomes. The differentiation between asthma, chronic obstructive pulmonary disease and bronchiectasis in the early stage of disease is extremely important for the adoption of appropriate therapeutic measures. However, because of the high prevalence of these diseases and the common pathophysiological pathways, some patients with different diseases may present with similar symptoms. The objective of this review is to highlight the similarities and differences between these diseases in terms of the risk factors, pathophysiology, symptoms, diagnosis and treatment.     

CD59a deficiency exacerbates influenza-induced lung inflammation through complement-dependent and -independent mechanisms

Influenza-specific immune activity not only promotes virus clearance but also causes immunopathology, thereby underlining the importance of mounting a measured anti-viral immune response. Since complement bridges both the innate and adaptive immune systems and has been implicated in defence against influenza, the role of the complement regulator CD59a in modulating the response to influenza was explored. For this purpose, immune responses to influenza virus, strain E61-13-H17, in mice deficient in the complement regulator protein CD59a (Cd59a(-/-) mice) were compared to those in wild-type mice. The severity of lung inflammation was significantly enhanced in the lungs of Cd59a(-/-) mice with increased numbers of infiltrating neutrophils and CD4(+) T cells. When complement was inhibited using soluble complement receptor 1, the frequency of lung-infiltrating neutrophils in influenza-infected Cd59a(-/-) mice was much reduced whilst numbers of CD4(+) T cells remained unchanged. These results demonstrate that CD59a, previously defined as a complement regulator, modulates both the innate and adaptive immune response to influenza virus by both complement-dependent and -independent mechanisms.     

Cigarette smoke dissociates inflammation and lung remodeling in OVA-sensitized and challenged mice

We evaluated the effects of cigarette smoke (CS) on lung inflammation and remodeling in a model of ovalbumin (OVA)-sensitized and OVA-challenged mice. Male BALB/c mice were divided into 4 groups: non-sensitized and air-exposed (control); non-sensitized and exposed to cigarette smoke (CS), sensitized and air-exposed (OVA) (50 μg+OVA 1% 3 times/week for 3 weeks) and sensitized and cigarette smoke exposed mice (OVA+CS). IgE levels were not affected by CS exposure. The increases in total bronchoalveolar fluid cells in the OVA group were attenuated by co-exposure to CS, as were the changes in IL-4, IL-5, and eotaxin levels as well as tissue elastance (p<0.05). In contrast, only the OVA+CS group showed a significant increase in the protein expression of IFN-γ, VEGF, GM-CSF and collagen fiber content (p<0.05). In our study, exposure to cigarette smoke in OVA-challenged mice resulted in an attenuation of pulmonary inflammation but led to an increase in pulmonary remodeling and resulted in the dissociation of airway inflammation from lung remodeling.     

Bronchial Asthma and Airway inflammation

Inflammation Research -     

Effect of aerobic exercise on lung regeneration and inflammation in mice

Aerobic exercise is well recognized to be beneficial to physical and mental health. Many studies have shown that aerobic exercise can improve the human immune system, but whether it could affect lung regeneration and inflammation remained unclear. Bronchioloalveolar stem cells (BASCs) play a key role in lung regeneration and repair, but it is unclear whether aerobic exercise affects BASCs. Here, we randomly divided 8 weeks old male mice into three groups: the control group without any aerobic exercise; the rest group which received 2 weeks of aerobic exercise (running wheel training) plus 5 days’ rest, and the exercise group which received 2 weeks of aerobic exercise without any rest. Our data indicated that mice in the exercise group had significantly increased BASCs compared to the control group, such difference did not exist in the rest group. Furthermore, the immune profiling suggested that lung inflammation was slightly up-regulated in the exercise group, particularly the inflammatory monocytes and IL-17A⁺ T cells. In conclusion, we provide direct evidence showing that aerobic exercise can facilitate lung regeneration with mild inflammatory effect, this finding is of great importance in the current COVID-19 pandemic.     

Erythropoietin attenuates hyperoxia-induced lung injury by down-modulating inflammation in neonatal rats

This study was done to determine whether recombinant human erythropoietin (rhEPO) treatment could attenuate hyperoxia-induced lung injury, and if so, whether this protective effect is mediated by the down-modulation of inflammation in neonatal rats. Newborn Sprague Dawley rat pups were subjected to 14 days of hyperoxia (>95% oxygen) within 10 hr after birth. Treatment with rhEPO significantly attenuated the mortality and reduced body weight gain caused by hyperoxia. With rhEPO treatment, given 3 unit/gm intraperitoneally at 4th, 5th, and 6th postnatal day, hyperoxia- induced alterations in lung pathology such as decreased radial alveolar count, increased mean linear intercept, and fibrosis were significantly improved, and the inflammatory changes such as myeloperoxidase activity and tumor necrosis factor-alpha expression were also significantly attenuated. In summary, rhEPO treatment significantly attenuated hyperoxia-induced lung injury by down-modulating the inflammatory responses in neonatal rats.     

An approach for understanding the inflammation and cancer relationship

It is well known that persistent inflammatory conditions can induce the cancer formation. In fact, cytokines and chemokines play a crucial role in the promoting of angiogenesis, metastasis, and subversion of adaptive immunity. These proteins are involved in cancer-related inflammation and can represent a target for innovative diagnostic and therapeutic strategies useful to clinical studies.     

氨茶碱对慢性间断低氧大鼠气道炎症及肺组织氧化损伤拮抗作用的探讨

目的：探讨慢性低氧致气道炎症和肺组织氧化损伤的作用及氨茶碱对其的拮抗作用。方法： 成年雄性Wistar大鼠34只，随机分3组：对照组（n=10）、低氧组（n=12）、氨茶碱干预组（n=12）。检测各组大鼠血液及肺组织匀浆中肿瘤坏死因子-α（TNF-α） 、白细胞介素-10（IL-10）、脂质过氧化物（LPO）含量及超氧化物歧化酶（SOD）活性。结果： 与对照组相比，低氧组大鼠血液及肺组织匀浆TNF-α、IL-10、LPO含量显著增高（P<0.01），SOD活性显著降低（P<0.01），同时，肺组织匀浆TNF-α/IL-10增大（P<0.01）；与低氧组相比，氨茶碱干预组大鼠血液及肺组织匀浆TNF-α、LPO 含量显著降低（P<0.01），SOD活性、IL-10水平显著增高（P<0.01和P<0.05）。结论： （1）慢性低氧可引起气道炎症并介导肺组织氧化损伤；（2）氨茶碱具有抗炎和抗氧化作用。     

FK506 (tacrolimus) improves lung injury through inhibition of Fas-mediated inflammation

Objective To investigate whether FK506 (tacrolimus) can inhibit Fas- or A23187-induced interleukin (IL)-8 expression and cell death in A549 human alveolar epithelial cells, plus Fas-mediated acute lung injury in vivo. Methods Assays for IL-8, cell death, and caspase-3 activity were performed. A549 cells were treated with 25 μmol A23187 or 0.2 μg/ml agonistic anti-Fas antibody plus 5 ng/ml interferon-gamma (IFN-γ). Tacrolimus was treated at 0.1–10 ng/ml. For in vivo experiment, agonistic anti-Fas antibody (Jo2) at 2.5 μg/g was intratracheally instilled into C57BL/6 mice. Neutrophils and protein contents in bronchoalveolar lavage (BAL) fluid were measured within 24 h of instillation. Mice were orally treated with 32 mg/kg of tacrolimus 24 h and 1 h prior to instillation. Results Both Fas and A23187 caused significant IL-8 expression and cell death in A549 cells. Tacrolimus inhibited A23187-induced IL-8 expression alone while it protected all Fas-mediated responses. Mice instilled intratracheally with Jo2 at 2.5 μg/g had significant increases in neutrophils, protein contents in BAL fluid and in expression of chemoattractants for neutrophils. These increases were reversed by tacrolimus. Conclusions Tacrolimus serves as a therapeutic option for improving lung injury through inhibition of Fas-mediated inflammation. Received 7 November 2005; returned for revision 28 December 2005; accepted by G. Wallace 2 February 2006     

嗜酸粒细胞性支气管炎气道炎症病理特征的探讨

目的： 观察嗜酸粒细胞性支气管炎（EB）气道粘膜炎症的病理特征，并与咳嗽变异型哮喘（CVA）进行比较。 方法： 对11例EB患者行纤支镜支气管粘膜活检，并以10例正常对照、10例CVA和14例典型支气管哮喘的支气管粘膜标本作对照。光镜下测量各组气道粘膜上皮的基底膜厚度，并通过免疫组化和特殊染色技术，计算EB和CVA组气道粘膜固有层中炎症细胞（嗜酸粒细胞、肥大细胞、T淋巴细胞）的浸润密度。 结果： EB组支气管粘膜基底膜厚度［2.92 μm(2.10-6.50)μm］显著高于对照组［2.08 μm(1.62-3.40 μm)］, P<0.05，同时显著低于CVA组［5.64 μm (3.23-8.48 μm)］, P<0.05，而CVA组的基底膜厚度又显著低于典型哮喘组［9.08 μm (6.61-11.99 μm)］, P<0.01；EB组气道粘膜固有层可见肥大细胞和嗜酸粒细胞散在分布，浸润密度分别为［75 cells/mm2(35-112 cells/mm2)］和［7 cells/mm2(0-31 cells/mm2)］，显著低于CVA组［148 cells/mm2(34-200 cells/mm2)，114 cells/mm2(1-768 cells/mm2)］, P<0.05，淋巴细胞浸润密度无显著差异。 结论： EB是以嗜酸细胞浸润为特征，涉及多种炎症细胞的慢性气道炎症性疾病，但气道粘膜基底膜厚度显著低于CVA和典型哮喘，炎症细胞浸润程度低于CVA，均可能是EB缺乏气道高反应性的重要机制。     

Pseudomonas aeruginosa and lung function decline in patients with bronchiectasis

ObjectivesThe objective of this study was to analyse lung function decline over time in bronchiectasis, along with the factors associated with it.MethodsSpirometry was measured every year in this observational, prospective study in 849 patients from the Spanish Bronchiectasis Registry (RIBRON). The main outcome was the decline in the rate of forced expiratory volume during the first second (FEV1). To be included in this study, patients needed a baseline assessment and at least one subsequent assessment. FEV1 decline was analysed using a mixed-effects linear regression model adjusted for clinically significant variables.ResultsWe recruited 849 bronchiectasis patients with at least two annual lung function measurements (follow-up range 1–4 years). A total of 2262 lung function tests were performed (mean 2.66 per patient, range 2–5). Mean baseline FEV1 was 1.78 L (standard deviation (SD) 0.76; 71.3% predicted). Mean age was 69.1 (SD 15.4) years; 543 (64% women. The adjusted rates of FEV1 decline were –0.98% predicted/year (95% confidence interval (CI) –2.41 to –0.69) and –31.6 (95% CI –44.4 to –18.8) mL. The annual FEV1 decline was faster in those patients with chronic bronchial infection by Pseudomonas aeruginosa (–1.37% (52.1 mL) vs –0.37% (–24.6 mL); p < 0.001), greater age, increased number of severe exacerbations in the previous year and higher baseline FEV1 value.DiscussionIn patients with bronchiectasis, the annual rate of FEV1 decline was –31.6 mL/year and it was faster in older patients and those with chronic bronchial infection by P. aeruginosa, increased number of previous severe exacerbations and higher baseline FEV1 value.     

Airway inflammation in thunderstorm asthma.

BACKGROUND: Epidemics of acute asthma associated with thunderstorms occur intermittently worldwide, though airway inflammation during these acute episodes has not been characterized. The aim of this study was to characterize airway inflammation in thunderstorm asthma. METHODS: Cases were recruited after presentation to the emergency room with acute asthma immediately following a thunderstorm (n = 6). They were compared to two control groups: a group of atopic asthmatics that had presented with acute asthma to the emergency room prior to the thunderstorm (n = 12), and a second group of corticosteroid naive asthmatics who presented to the emergency room in the prior 12 months (n = 6). Subjects had spirometry, sputum induction and allergy skin tests acutely and at review 4 weeks later. RESULTS: Thunderstorm (TS) cases were more likely to have a history of hay fever and grass pollen allergy, and less likely to be on inhaled corticosteroids (ICS) prior to presentation. Cases and control groups had a similar degree of moderate to severe acute airway obstruction (P = 1.0). TS cases had elevated sputum eosinophils (14.8% of total cell count) compared to controls (1%, 2.6%, P < 0.01). TS cases had higher sputum eosinophil cationic protein (ECP; 11,686 ng/mL) compared to controls (1,883, 3,300, P = 0.02) acutely. TS cases had more cells positive for IL-5 (30%) compared to controls (1, 1.5%, P = 0.02). When adjusted for ICS use, TS cases had a risk ratio for elevated sputum eosinophils of 2.4 (1.23-4.69). CONCLUSION: Thunderstorm asthma is characterized by airway inflammation with IL-5-mediated sputum eosinophilia and eosinophil degranulation. These results are consistent with allergen exposure as the cause of the exacerbation, and are consistent with the thunderstorm-induced grass pollen deluge as the cause of epidemic asthma after thunderstorms.     

Th17细胞在慢性阻塞性肺疾病肺部炎症中的作用

由于长期吸烟的刺激,活化的辅助性T细胞17（Th17）能浸润到肺组织并参与肺泡壁的破坏及肺气肿的形成.Th17细胞在IL-23的作用下,分泌IL-17、IL-21、IL-22等多种细胞因子,其中IL-17可以促进气道中性粒细胞的募集和激活,IL-21在维持、增强Th17细胞的数量及功能的同时,能增加CD8＋细胞的数量及其细胞毒活性,在吸烟诱导的慢性阻塞性疾病（COPD）肺部连续炎症中发挥持续放大效应.在不同的炎症环境中,Th17细胞及其分泌的细胞因子与Th1细胞、调节性T细胞（Treg）以及多种参与固有免疫应答的细胞间相互作用和调节,共同参与COPD的发病,并构成了固有免疫与适应性免疫之间的桥梁.     

Airway inflammation and cough sensitivity in cough-variant asthma

BACKGROUND: Mechanisms underlying cough and bronchoconstriction in patients with cough-variant asthma (CVA) are not well established. Differences in location or degree of activation of eosinophils and allergic cytokines have been suggested as the likely causes. To address this issue, we have carried out a comparative study of airway inflammatory markers between patients with CVA and classic asthma (CA). The relationship between these markers with airway hyperresponsiveness (AHR) and cough sensitivity has also been studied. METHODS: Twenty-seven non-smokers and steroid-naive patients with CVA (12) and CA (15) were examined. Capsaicin challenge, histamine bronchoprovocation test, nitric oxide levels in exhaled air and sputum induction were performed in all of them. Differential cell sputum recount and supernatant concentrations of eosinophil granule-derived cationic proteins (ECP), interleukin (IL)5, IL8 and tumour necrosis factor (TNF)-alpha were also measured. RESULTS: There were no significant differences in either the inflammatory pattern of soluble markers or differential cell counts between CA and CVA. Histamine PC20 was correlated with IL-5 in CVA, whereas it was associated with sputum eosinophilia in CA. Cough sensitivity (log C5) and histamine PC20 were inversely related in CA. CONCLUSIONS: Although the pattern of inflammatory sputum markers in patients with asthma and cough-variant asthma is similar, its relation with bronchial hyperreactivity and cough sensitivity is different in each group.