Significant Role of Interleukin-8 in Pathogenesis of Pulmonary Disease Due to Mycoplasma pneumoniae Infection

We found elevated levels of interleukin-8 in pleural fluid samples from patients with pleural effusion and with a sustained fibrotic change of the lung due to Mycoplasma pneumoniae infection. This result suggests a critical role of interleukin-8 in the pathogenesis of a certain type of pulmonary disease caused by M. pneumoniae.     

Chlamydia pneumoniae Infection in Acute Exacerbations of Chronic Obstructive Pulmonary Disease: Analysis of 250 Hospitalizations

Two hundred fifty hospitalizations were included in a serologically based prospective study to assess the role of Chlamydia pneumoniae in episodes of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and the percentage of COPD patients chronically infected with this pathogen. Chlamydia pneumoniae-specific IgG, IgA and IgM antibody titers were determined using a commercial kit with the microimmunofluorescence method. A significantly higher geometric mean titer in the COPD patients compared to the control group was found for IgG (P<0.00001) and IgA (P<0.000001). The serological criterion for chronic Chlamydia pneumoniae infection (IgG ≥128 concomitant with IgA ≥64) was positive in 73 (33.3%) COPD patients compared with 7 (7%) controls (P=0.000001). No difference was found in any serological parameter when the study population was divided by severity of COPD. When the serological profiles were compared between the first and second of 31 pairs of hospitalizations, 7 of the 62 (11.3%) hospitalizations showed evidence of acute infection with Chlamydia pneumoniae around one of the episodes of AECOPD. It is concluded that compared with the control group, the COPD patients had a significantly higher prevalence of chronic Chlamydia pneumoniae infection. In the COPD group, there was no correlation between the severity of the disease and the rate of chronic Chlamydia pneumoniae infection. In a substantial percentage of AECOPD cases, there is serological evidence of acute Chlamydia pneumoniae infection around the time of the exacerbation. The clinical and pathophysiologic implications of these findings should be clarified by further studies. Electronic Publication     

Oral Lovastatin Attenuates Airway Inflammation and Mucus Secretion in Ovalbumin-Induced Murine Model of Asthma

Purpose

Lovastatin is an effective inhibitor of cholesterol synthesis. A previous study demonstrated that lovastatin can also suppress airway hyperresponsiveness (AHR) in murine model of asthma. We aimed to investigate the effect of lovastatin on mucus secretion and inflammation-associated gene expression in the lungs of murine model of asthma.

Methods

Female BALB/c mice were sensitized and challenged with ovalbumin (OVA) by intraperitoneal injection, and orally administered lovastatin from days 14 to 27 post-injection. Gene expression in lung tissues was analyzed using real-time polymerase chain reaction. AHR and goblet cell hyperplasia were also examined. BEAS-2B human bronchial epithelial cells were used to evaluate the effect of lovastatin on the expression of cell adhesion molecules, chemokines, and proinflammatory cytokines in vitro.

Results

We showed that lovastatin inhibits the expression of Th2-associated genes, including eotaxins and adhesion molecules, in the lungs of murine model of asthma. Mucin 5AC expression, eosinophil infiltration and goblet cell hyperplasia were significantly decreased in the lung tissue of murine model of asthma treated with lovastatin. Furthermore, lovastatin inhibited AHR and expression of Th2-associated cytokines in bronchoalveolar lavage fluid. However, a high dose (40 mg/kg) of lovastatin was required to decrease specific IgE to OVA levels in serum, and suppress the expression of Th2-associated cytokines in splenocytes. Activated BEAS-2B cells treated with lovastatin exhibited reduced IL-6, eotaxins (CCL11 and CCL24), and intercellular adhesion molecule-1 protein expression. Consistent with this, lovastatin also suppressed the ability of HL-60 cells to adhere to inflammatory BEAS-2B cells.

Conclusions

These data suggest that lovastatin suppresses mucus secretion and airway inflammation by inhibiting the production of eotaxins and Th2 cytokines in murine model of asthma.     

Comparison of PCR, Culture, and Serological Tests for Diagnosis of Mycoplasma pneumoniae Respiratory Tract Infection in Children

For diagnosis of Mycoplasma pneumoniae infection we compared two rapid tests, PCR and the immunoglobulin M immunofluorescence assay (IgM IFA), with culture and the complement fixation test (CFT), in a prospective study among 92 children with respiratory tract infection and 74 controls. Based on positivity of culture and/or CFT as the diagnostic criterion, nine patients (10%) were diagnosed with M. pneumoniae infection. All patients positive by culture were also positive by PCR. In all controls cultures, PCRs, and serological assays were negative, except in one with a positive IgM IFA. The IgM IFA had a low positive predictive value of 50%. Only a combination of PCR (seven patients) and CFT (seven patients) allowed diagnosis of all cases.     

Development and Characterization of a Long-Term Murine Model of Streptococcus pneumoniae Infection of the Lower Airways

Chronic obstructive pulmonary disease (COPD) is characterized by long periods of stable symptoms, but exacerbations occur, which result in a permanent worsening of symptoms. Previous studies have shown a link between bacterial colonization of the lower airways of COPD sufferers and an increase in exacerbation frequency. One of the most frequent bacterial colonizers is Streptococcus pneumoniae. To mimic this aspect of COPD, a murine model of low-level pneumococcal colonization in the lung has been developed, in which S. pneumoniae persisted in the lungs for at least 28 days. From day 14 postinfection, bacterial numbers remained constant until at least 28 days postinfection, and animals showed no outward signs of disease. The bacterial presence correlated with a low-level inflammatory response that was localized to small foci across the left and inferior lobes of the lung. The cellular response was predominantly monocytic, and focal fibroplasia was observed at the airway transitional zones. Physiological changes in the lungs were investigated with a Forced Maneuvers system. This new model provides a means of study of a long-term pulmonary infection with a human pathogen in a rodent system. This is an excellent tool for the development of future models that mimic complex respiratory diseases such as COPD and asthma.     

Artificial Intelligence and Machine Learning in Chronic Airway Diseases: Focus on Asthma and Chronic Obstructive Pulmonary Disease

Chronic airway diseases are characterized by airway inflammation, obstruction, and remodeling and show high prevalence, especially in developing countries. Among them, asthma and chronic obstructive pulmonary disease (COPD) show the highest morbidity and socioeconomic burden worldwide. Although there are extensive guidelines for the prevention, early diagnosis, and rational treatment of these lifelong diseases, their value in precision medicine is very limited. Artificial intelligence (AI) and machine learning (ML) techniques have emerged as effective methods for mining and integrating large-scale, heterogeneous medical data for clinical practice, and several AI and ML methods have recently been applied to asthma and COPD. However, very few methods have significantly contributed to clinical practice. Here, we review four aspects of AI and ML implementation in asthma and COPD to summarize existing knowledge and indicate future steps required for the safe and effective application of AI and ML tools by clinicians.     

IL‐33 Receptor (ST2) Signalling is Important for Regulation of Th2‐Mediated Airway Inflammation in a Murine Model of Acute Respiratory Syncytial Virus Infection

T1/ST2, an orphan receptor with homology with the interleukin (IL)‐1 receptor family, is the ligand‐binding component of the receptor for the cytokine IL‐33, a newly identified cytokine known to amplify the Th2 cell‐dominant immune responses. The function of IL‐33/ST2 signalling during respiratory syncytial virus (RSV) infection is not fully known. In this study, following intranasal infection with RSV, BALB/c mice showed a marked increase in the production of IL‐33, with an elevated expression of ST2 mRNA as well as a massive infiltration of CD45⁺ST2⁺ cells in the lungs, suggesting that during the early phase of RSV infection, IL‐33 target cells which express ST2 on cell surface, may play a critical role for the development of RSV‐induced airway inflammation. Indeed, blocking ST2 signalling using anti‐ST2 monoclonal antibody diminished not only RSV‐induced eosinophil recruitment, but also the amounts of Th2‐associated cytokines, particularly IL‐13, and Th17‐type cytokine IL‐17A in the lungs of infected mice. However, anti‐ST2 antibody treatment did not affect the production of Th1‐type cytokine IFN‐γ as well as pulmonary viral growth and clearance. These results indicate that IL‐33/ST2 signalling is involved in RSV‐induced, Th2‐associated airway inflammation but not protective immunity.     

Close Association between Pulmonary Disease Manifestation in Mycoplasma pneumoniae Infection and Enhanced Local Production of Interleukin-18 in the Lung, Independent of Gamma Interferon

To investigate pathophysiologies of Mycoplasma pneumoniae infection from an immunological point of view, we measured the levels of interleukin-18 (IL-18) (originally designated gamma interferon [IFN-γ]-inducing factor) in 19 serum samples from 10 patients with pneumonia without pleural effusion (ages 1 to 16 years), 3 serum and 13 pleural fluid samples from 11 patients with pleural effusions (ages 11 months to 15 years), and 18 serum and 27 cerebrospinal fluid samples from 24 patients with central nervous system complications (ages 1 to 15 years). IL-18 was measured by a commercially available enzyme-linked immunosorbent assay kit (MBL, Nagoya, Japan). In addition, the levels of tumor necrosis factor alpha, IFN-γ, IL-6, IL-12, and KL-6 (a mucin-like glycoprotein expressed on type 2 pneumocytes) were measured in selected samples. The results concerning pleural effusions showed that elevated levels of IL-18 in pleural fluid, but not in serum, were solely associated with a sustained fibrotic change of the lung on chest roentgenography which might represent a pathological feature of intraluminal organization. All the pleural fluid samples with elevated levels of IL-18 were positive by PCR for M. pneumoniae DNA. There was no association between IL-18 and IFN-γ levels in serum or in the pleural fluid. On the other hand, elevated levels of IL-18 in serum, but not in cerebrospinal fluid samples, were observed in the cases complicated by central nervous system involvement, including profound brain dysfunction with seizures. Our study demonstrated that M. pneumoniae can induce IL-18 and that the enhanced local production of IL-18 in the lung is closely associated with pulmonary disease manifestation.     

Allergic Airway Inflammation Decreases Lung Bacterial Burden following Acute Klebsiella pneumoniae Infection in a Neutrophil- and CCL8-Dependent Manner

The Th17 cytokines interleukin-17A (IL-17A), IL-17F, and IL-22 are critical for the lung immune response to a variety of bacterial pathogens, including Klebsiella pneumoniae. Th2 cytokine expression in the airways is a characteristic feature of asthma and allergic airway inflammation. The Th2 cytokines IL-4 and IL-13 diminish ex vivo and in vivo IL-17A protein expression by Th17 cells. To determine the effect of IL-4 and IL-13 on IL-17-dependent lung immune responses to acute bacterial infection, we developed a combined model in which allergic airway inflammation and lung IL-4 and IL-13 expression were induced by ovalbumin sensitization and challenge prior to acute lung infection with K. pneumoniae. We hypothesized that preexisting allergic airway inflammation decreases lung IL-17A expression and airway neutrophil recruitment in response to acute K. pneumoniae infection and thereby increases the lung K. pneumoniae burden. As hypothesized, we found that allergic airway inflammation decreased the number of K. pneumoniae-induced airway neutrophils and lung IL-17A, IL-17F, and IL-22 expression. Despite the marked reduction in postinfection airway neutrophilia and lung expression of Th17 cytokines, allergic airway inflammation significantly decreased the lung K. pneumoniae burden and postinfection mortality. We showed that the decreased lung K. pneumoniae burden was independent of IL-4, IL-5, and IL-17A and partially dependent on IL-13 and STAT6. Additionally, we demonstrated that the decreased lung K. pneumoniae burden associated with allergic airway inflammation was both neutrophil and CCL8 dependent. These findings suggest a novel role for CCL8 in lung antibacterial immunity against K. pneumoniae and suggest new mechanisms of orchestrating lung antibacterial immunity.     

The Role of Thymic Stromal Lymphopoietin in Allergic Inflammation and Chronic Obstructive Pulmonary Disease

Thymic stromal lymphopoietin (TSLP) primes dendritic cells to promote a Th2 inflammatory response. Its action is mediated by a heterodimeric receptor which consists of the interleukin-7 receptor α chain and the TSLP receptor chain (TSLPR). TSLPR resembles the common γ chain subunit utilized by many type 1 cytokine receptors. Normal epithelial cells, keratinocytes, and stromal cells constitutively express TSLP. Dendritic cells that are activated by TSLP promote the development of CD4⁺ T cells into pro-inflammatory Th2 cells. TSLP thus plays a potentially important role in the pathogenesis of allergic inflammation in asthma and atopic dermatitis. TSLP also has direct effects on other types of cells in the bronchial mucosa. It is over-expressed in the bronchial mucosa in chronic obstructive pulmonary disease (COPD), which is traditionally described as a Th1-related disease, as well as severe asthma, which is traditionally described as a Th2-related disease. In this review we will discuss TSLP expression, function, and available and potential mechanisms in both allergic inflammation and COPD.     

双水平正压通气对慢阻肺患者行椎管内麻醉及手术时呼吸功能的影响

目的探讨双水平正压通气对慢性阻塞性肺疾病（COPD）患者在椎管内麻醉及手术中呼吸支持的效果。方法选择23例COPD合并Ⅱ型呼吸衰竭拟行下腹部或下肢手术的患者,腰-硬联合麻醉后行双水平正压（BiPAP）通气,BiPAP呼吸机采用S／T模式,设定呼吸频率为15次／min,吸气相压力（IPAP）为10～16cmH2O,呼气相压力（EPAP）为4cmH2O,吸入氧浓度为50％。监测无创血压、呼吸、心电图、脉搏氧饱和度、麻醉前、BiPAP通气后1h及脱机30min后的动脉血气值。结果患者BiPAP通气后动脉血二氧化碳分压（PaCO2）显著降低,从（62．6±13．1）mmHg降至（51．0±8．7）mmHg（P〈0．01）;动脉血氧分压（PaO2）显著增高,从（54．3±12．2）mmHg升至（71．4±14．5）mmHg（P〈0．01）;动脉血pH显著增高,从（7.31±0．09）升至（7．39±0．07）,（P〈0．01）;脱离BiPAP通气30min后动脉血气比麻醉前基础水平略有改善,但差异无统计学意义（P〉0．05）。结论双水平正压通气可明显改善COPD患者在低平面阻滞麻醉及手术期呼吸功能。     

Relationship of Pneumocystis jiroveci Humoral Immunity to Prevention of Colonization and Chronic Obstructive Pulmonary Disease in a Primate Model of HIV Infection

Pulmonary colonization by the opportunistic pathogen Pneumocystis jiroveci is common in HIV⁺ subjects and has been associated with development of chronic obstructive pulmonary disease (COPD). Host and environmental factors associated with colonization susceptibility are undefined. Using a simian-human immunodeficiency virus (SHIV) model of HIV infection, the immunologic parameters associated with natural Pneumocystis jiroveci transmission were evaluated. SHIV-infected macaques were exposed to P. jiroveci by cohousing with immunosuppressed, P. jiroveci-colonized macaques in two independent experiments. Serial plasma and bronchoalveolar lavage (BAL) fluid samples were examined for changes in antibody titers to recombinant Pneumocystis-kexin protein (KEX1) and evidence of Pneumocystis colonization by nested PCR of BAL fluid. In experiment 1, 10 of 14 monkeys became Pneumocystis colonized (Pc⁺) by 8 weeks post-SHIV infection, while 4 animals remained Pneumocystis colonization negative (Pc⁻) throughout the study. In experiment 2, 11 of 17 animals became Pneumocystis colonized by 16 weeks post-SHIV infection, while 6 monkeys remained Pc⁻. Baseline plasma KEX1-IgG titers were significantly higher in monkeys that remained Pc⁻, compared to Pc⁺ monkeys, in experiments 1 (P = 0.013) and 2 (P = 0.022). Pc⁻ monkeys had greater percentages of Pneumocystis-specific memory B cells after SHIV infection compared to Pc⁺ monkeys (P = 0.037). After SHIV infection, Pc⁺ monkeys developed progressive obstructive pulmonary disease, whereas Pc⁻ monkeys maintained normal lung function throughout the study. These results demonstrate a correlation between the KEX1 humoral response and the prevention of Pneumocystis colonization and obstructive lung disease in the SHIV model. In addition, these results indicate that an effective Pneumocystis-specific memory B-cell response is maintained despite progressive loss of CD4⁺ T cells during SHIV infection.Despite advances in treatment strategies and the introduction of antiretroviral therapy (ART), pulmonary diseases remain a leading cause of morbidity and mortality in HIV-infected patients (34). Both emphysema and chronic obstructive pulmonary disease (COPD) have been reported at an increased frequency in HIV-infected patients (7, 15) and, unlike many AIDS-associated opportunistic infections, HIV-associated COPD may be increasing due to the prolonged life expectancy of the HIV⁺ population with ART and the high smoking rate in this population (5, 24). Although cigarette smoking is a primary risk factor for the development of COPD, it is interesting that HIV⁺ nonsmokers may also be at increased risk of disease (14). In addition, the observation that most smokers do not develop COPD (33) indicates that other factors may play a role in disease development.Evidence has accumulated suggesting a role for infectious agents as cofactors in the pathogenesis and exacerbation of COPD (58), where pulmonary inflammation due to cigarette smoke may be amplified by the presence of persistent infectious agents. The chronic inflammation associated with infectious agents is also thought to contribute to the development of COPD in HIV⁺ patients (44, 58). This possibility is highlighted by the observation that HIV-infected patients may be more prone to develop subclinical lung infections even if successfully treated with ART (16).Our laboratory and others have accumulated evidence in humans and in animal models that the fungal opportunistic pathogen, Pneumocystis jiroveci (formerly Pneumocystis carinii f. sp. hominis) is an important pathogen in COPD in both HIV⁺ and HIV⁻ populations. COPD-like changes have been reported in HIV⁺ patients with Pneumocystis pneumonia (PcP) (45), and recent studies suggest that low-level asymptomatic carriage of Pneumocystis may be associated with lung damage. An increased frequency of Pneumocystis colonization has been reported in HIV⁺ patients, including those on ART (41), and we have recently shown that HIV⁺ subjects who were Pneumocystis colonized (Pc⁺) have worse airway obstruction than HIV⁺ subjects who were Pc⁻ (40). An association between Pneumocystis colonization and COPD has also been shown in HIV⁻ subjects (3, 52).Animal models also support the role of Pneumocystis colonization in the pathogenesis of COPD. In a model of immunocompetent mice, cigarette exposure and Pneumocystis colonization resulted in greater pulmonary function deficits compared to cigarette exposure alone (4). Our laboratory has reported that in a simian immunodeficiency virus (SIV)-primate model of HIV infection, Pneumocystis colonization results in pulmonary inflammation, pulmonary function deficits, and anatomic emphysema (2, 6, 47, 59). Factors that influence susceptibility to Pneumocystis colonization are not clearly understood.Immunologic control of Pneumocystis infection is strongly correlated with CD4⁺ T-cell responses, although B cells and antibodies also play a role in prevention of PcP (19-23, 25, 38, 62). There is a high frequency of Pneumocystis-specific seroprevalence in immunocompetent adults (1, 9), as well as in nonhuman primates (11, 30), suggesting the persistence of serological memory or Pneumocystis-specific, long-lived plasma cells in response to natural Pneumocystis exposure. Antibodies to the Pneumocystis endoprotease kexin (KEX1) may be particularly important, because immune responses to Pneumocystis KEX1 have been associated with control of Pneumocystis infection in immunosuppressed murine models (62, 63).In the present study, we investigated the capacity of simian/human immunodeficiency virus (SHIV)-infected macaques to generate a humoral immune response to KEX1 in response to natural Pneumocystis exposure and examined the relationship between anti-Pneumocystis humoral immunity, the development of Pneumocystis colonization, and the development of COPD.(This study was presented in part as a poster at the American Thoracic Society International Conference, New Orleans, LA, 14 to 19 May 2010, and the American Thoracic Society International Conference, Toronto, Canada, 16 to 21 May 2008. A portion of the study was also presented as an oral presentation at the International Workshops on Opportunistic Protists in Boston, MA, 28 to 31 May 2008).     

Environmental Tobacco Smoke and Progesterone Alter Lung Inflammation and Mucous Metaplasia in a Mouse Model of Allergic Airway Disease

The prevalence and severity of asthma is sexually dimorphic. Adult women have a higher incidence of asthma than men. This suggests that this disease may have a hormonal component. Progesterone has been shown to elicit an immune response similar to that seen in allergic asthma and previous studies have shown that progesterone increases total IgE levels in the peripheral blood. In the current study, we examine the effect of environmental tobacco smoke (ETS) and progesterone on hallmarks of asthma pathology in lung tissue with the goal of defining whether progesterone can also exacerbate two key features of airway remodeling: accumulation of eosinophils and increased mucous. We used a mouse model of allergic asthma that includes house dust mite allergen (HDMA). Adult female BALB/c mice were ovariectomized and implanted with time-release progesterone pellets. Mice were housed in filtered air or ETS for 6 weeks (1 mg/m3 total suspended particulate) and exposed to HDMA by inhalation. Progesterone alone did not increase mucous cell mass or the abundance of eosinophils but ETS coupled with progesterone exposure resulted in a significant increase in mucous cell metaplasia and increased accumulation of eosinophils in the asthma model. Levels of cytokines in the bronchoalveolar lavage fluid, measured using a multiplex cytokine assay, revealed elevated levels of both interleukin (IL)-5 and IL-12(p40) in HDMA-exposed animals. The addition of progesterone further exacerbated this response. We conclude that progesterone, in the absence of estrogen, exacerbates airway inflammation and airway remodeling induced by the toxicant ETS.     

Construction of Risk Prediction Model of Cardiac Arrest in Patients with Chronic Obstructive Pulmonary Disease Complicated with Respiratory Failure

Objective: To construct a risk prediction model for in-hospital cardiac arrest(IHCA) in patients with chronic obstructive pulmonary disease(COPD) complicated with respiratory failure. Methods: The clinical data of 550 patients with COPD complicated with respiratory failure in our hospital from January 2016 to June 2022 were retrospectively analyzed. According to the occurrence of IHCA, they were divided into the IHCA group and non-IHCA group. The general data and clinical indicators of the two g...