Microbiota-dependent mechanism of Jianpiyifei II in treating experimental virus-induced acute exacerbation of chronic obstructive pulmonary disease.

Objective To compare phlegm-heat syndrome(痰热证)with phlegm-dampness syndrome(痰湿证)of acute exacerbation of chronic obstructive pulmonary disease(AECOPD)in regard to inflammatory response,hormone level,lung pathological examination and lung function.Methods Fifty-six Wistar rats were randomly divided into four groups,including normal control group,AECOPD group,phlegm-heat syndrome of AECOPD group(PHs group),phlegm-dampness syndrome of AECOPD group(PDs group).The level of white blood cell(WBC)count,neutrophil ratio,free triiodothyronine(FT3),free thyroxine(FT4),epinephrine(E),norepinephrine(NE),cortisol(COR),C-reactive protein(CRP),tumor necrosis factor-α(TNF-α),interleukin-8(IL-8)in blood,and TNF-α,IL-8,intercellular adhesion molecule-1(ICAM-1)in broncho-alveolar lavage fluid(BALF)were determined with radioimmunology.Lung function was tested by whole-body plethysmography.Results ①The count of WBC and neutrophil ratio in PDs group were higher than in PHs group,AECOPD group and normal group,there was significant difference in multiple comparison.The levels of inflammatory mediators in serum and BALF in three model groups were evidently higher than in normal group,and IL-8[(4.13±1.28)μg／L]and CRP((3.07±0.69)μg／L]in serum in PDs group were higher than those in PHs group (1.75±0.53)μg／L,(1.98±0.42)μg／L,both P<0.01].②FT3 level in blood in both AECOPD group and PHs group [(9.44±3.17)pmol／L,(9.95±3.68)pmol／L]was significantly higher than that in normal control group[(4.53±2.80)pmol／L],FT3 in PDs group[(2.13±1.31)pmol／L]was evidently lower than that in normal group(p<0.05 or P<0.01).The level of FT4[(2.23±0.71)pmol／L],E[(87.27±29.32)nmol／L]and NE[(71.69±21.24)nmol／L] in PDs group were all obviously lower than those in normal group[FT4:(4.64±1.49)pmol／L,E:(143.94±32.90)nmol／L,NE:(100.32±27.73)nmol／L,P<0.05 or P<0.01].There was no significant difference in the above three parameters between AECOPD group and normal group.Each parameter in PHs group was markedly higher than that in AECOPD group.The content of COR in PDs group was higher than in PHs group, in which COR was higher than in AECOPD group,which was equal to that in normal group. ③The pathological changes in lung included inflammatory cell infiltration, exfoliation of cilia, dilatation of alveolar spaces of lung tissue in AECOPD group, which were more significant in PHs group and PD group. Inflammatory cells infiltration around the bronchi, thickening of interalveolar spaces, and vasodilatation were more pronounced in PHs group and PDs group than in AECOPD group. Inflammatory cell infiltration around the bronchi were about the same between PHs and PDs groups. ④The levels of peak expiratory velocity (PEV), tidal volume (VT), minute ventilation (MV)were significantly lower in AECOPD group, PHs group and PDs group than in normal control group, but the levels of frequency (f) and inspiratory resistance (Rin) were evidently higher. Compared with AECOPD group, the levels of PEV, VT, MV were significantly decreased, the level of respiratory f and Rin evidently increased in PDs group. Compared with PHs group, the levels of PEV, VT, MV significantly decreased in PDs group, while the level of f and Rin evidently increased. There was no significant difference in the above five parameters between AECOPD group and PHs group. Conclusion The changes in local and systemic inflammatory response, lung histopathological injury in PHs group and PDs group were more evident than changes in AECOPD group. The changes in systemic inflammatory response, decrease in functional indicators of thyroid and adrenal medulla, and decline in lung function were more marked in PDs group than in PHs group. Key words: Chronic obstructive pulmonary disease; Acute exacerbation; Phlegm-heat syndrome; Phlegm-dampness syndrome; Animal model

Respiratory virus infections are associated with chronic obstructive pulmonary disease (COPD) exacerbations, but a causative relationship has not been proven. Studies of naturally occurring exacerbations are difficult and the mechanisms linking virus infection to exacerbations are poorly understood. We hypothesized that experimental rhinovirus infection in subjects with COPD would reproduce the features of naturally occurring COPD exacerbations and is a valid model of COPD exacerbations. To evaluate experimental rhinovirus infection as a model of COPD exacerbation and to investigate the mechanisms of virus-induced exacerbations. We used experimental rhinovirus infection in 13 subjects with COPD and 13 nonobstructed control subjects to investigate clinical, physiologic, pathologic, and antiviral responses and relationships between virus load and these outcomes. Clinical data; inflammatory mediators in blood, sputum, and bronchoalveolar lavage; and viral load in nasal lavage, sputum, and bronchoalveolar lavage were measured at baseline and after infection with rhinovirus 16. After rhinovirus infection subjects with COPD developed lower respiratory symptoms, airflow obstruction, and systemic and airway inflammation that were greater and more prolonged compared with the control group. Neutrophil markers in sputum related to clinical outcomes and virus load correlated with inflammatory markers. Virus load was higher and IFN production by bronchoalveolar lavage cells was impaired in the subjects with COPD. We have developed a new model of COPD exacerbation that strongly supports a causal relationship between rhinovirus infection and COPD exacerbations. Impaired IFN production and neutrophilic inflammation may be important mechanisms in virus-induced COPD exacerbations.

Matrix metalloproteinase-12 (MMP-12) and Tissue inhibitor of metalloproteinase-4 (TIMP-4) play important roles in the pathophysiology of chronic obstructive pulmonary disease (COPD). Subjects of many previous studies were patients with severe and very severe COPD. However, there are comparatively few studies on patients with mild-to-moderate COPD. Our aim was to measure MMP-12 and TIMP-4 levels and to compare its levels in various materials in patients with mild-to-moderate acute exacerbation of chronic obstructive pulmonary disease (AECOPD). We also compared which of the two materials of these biomarkers was better correlated with disease severity and DODE index. A total of 39 patients with AECOPD and 25 control subjects were enrolled in our study. MMP-12 and TIMP-4 in different respiratory samples were detected by ELISA. Expression levels of MMP-12 in bronchoalveolar lavage fluid (BALF) and exhaled breath condensate (EBC) and TIMP-4 in BALF were significantly higher in AECOPD patients than that in healthy subjects (P < 0.001). However, there was no significant difference in TIMP-4 level in EBC of AECOPD patients compared to healthy subjects (P = 0.0527). The levels of MMP-12 in BALF and EBC and TIMP-4 in BAFL of AECOPD patients were significantly correlated with FEV1% predicted (P < 0.001). However, in AECOPD patients, there was no significant correlation between TIMP-4 levels in EBC and BODE index (r = 0.4175, P = 0.0559). During mild-to-moderate AECOPD, the levels of MMP-12 and TIMP-4 in BALF were better correlated with FEV1% predicted and BODE index than that in EBC, indicating that they may be new target interventions for pharmacology to prevent and/or treat AECOPD.

Triple therapy with inhaled corticosteroid (ISC) / long-acting β2 agonist (LABA) / long-acting muscarinic antagonist (LAMA) in single inhaler expanded the possibilities for prevention of chronic obstructive pulmonary disease (COPD) exacerbations. Heterogeneity of COPD determines the needs in search of target population and efficacy markers for each existing therapy. Disease phenotype depends on a complex of factors, with respiratory viral infection among the most significant. Aim of the study was to assess the efficacy of triple therapy with ICS/LABA/LAMA in single inhaler for subsequent COPD exacerbations prevention and to search molecular markers of the efficacy depending the etiology of index exacerbation. Material and methods. It was a prospective observational study of three COPD patients’ strata: after COPD exacerbation required hospitalization with viral (n = 60), bacterial (n = 60) and viral-bacterial (n = 60) infection. Triple therapy in single inhaler (n = 104) or in free combinations (n = 76) were prescribed in real clinical practice. COPD was diagnosed according to spirography criteria. To establish the COPD exacerbation etiology the real time PCR of sputum or bronchoalveolar lavage fluid, standard cultural method, blood procalcitonin, as well as marker blood proteins, hyaluronic acid by ELISA measurement were done. Associations were revealed using Cox regression. Results. Triple therapy in single inhaler in comparison with free combinations decreased time to first re-exacerbation, hazard ratio (HR) in viral-associated index exacerbation strata was 0.38 (95% confidence interval (95% CI) 1.15–0.40), in bacterial – 0.47 (0.39–0.72), in viral-bacterial – 0.39 (0.14–0.39). In strata of COPD patients after viral and viral-bacterial exacerbations, in subgroups treated with triple therapy in single inhaler blood procollagen III N-terminal propeptide (PIIINP) (HR for group after viral index exacerbations was 1.03, 95 % CI 1.02–1.28, HR for group after viral-bacterial exacerbations was 1.04, 95 % CI 1.02–1.28), granulocyte-macrophage colony-stimulating factor (GM-CSF) (HR 1.03, 95 % CI 1.02–1.32, 1.01, 95 % CI 1.00–1.35, respectively) content was associated with time of re-exacerbations. Conclusions. Blood PIIINP and GM-CSF during COPD exacerbation are perspective markers of subsequent exacerbations within 1 year in patients after virus-associated or viral-bacterial index exacerbation. In these groups of patients triple therapy in single inhaler is more effective than free combination for subsequent exacerbations prevention.

How Viral Infections Cause Exacerbation of Airway Diseases

Background: Community-acquired pneumonia is a differential diagnosis of acute exacerbation of chronic obstructive pulmonary disease (COPD); further both have similar pathogenic spectra. Both the American Thoracic Society and the European Respiratory Society follow similar empirical antibiotic choices for the two conditions. However, there are some differences in the bacterial spectra between the two conditions, particularly when the severity of the disease differs. In the present study, we want to study the differences in the clinical features, bacteriological spectra, and antibiotic susceptibilities in patients with community-acquired pneumonia versus patients with COPD exacerbation and provide a scientific basis for antibiotic selection. Aims: 1. To analyze the differences in the pathogenic spectra and antibiotic sensitivity profile between COPD exacerbation and community acquired pneumonia. 2. To study the differences in the clinical features and outcomes of the two conditions. Subjects and Methods: The study was a prospective observational study conducted from November 2019 to May 2020 in Bangalore Medical College and Research Institute on 30 patients diagnosed with acute exacerbation of COPD and 30 patients diagnosed with community acquired pneumonia. Detailed history, physical examination, and standard laboratory tests were taken on admission. The presence of new consolidation on chest radiograph was recorded. Sputum specimens collected by expectoration and tracheal suctioning or bronchoalveolar lavage were analyzed by Gram staining and microscopy and also by culture. The isolates were also tested for antibiotic sensitivity. The severity of Chronic obstructive pulmonary disease (COPD) exacerbation was assessed by the DECAF score and the severity of the CAP group was assessed by the Pneumonia Severity Index. The differences between the two groups were analyzed. The progression of the disease and the outcomes were observed. Results: Out of 30 (100%) participants in each group, both pneumonia and COPD participants had higher percentage of male participants; 24 (80%) and 26 (86.7%) participants, respectively. The COPD-exacerbation group was significantly older than the community-acquired pneumonia group (63.20 ± 11.82 vs. 43.73 ± 16.58). Klebsiella pneumoniae, Pseudomonas, Streptococcus pneumoniae, and Escherichia Coli were the most commonly isolated species in COPD subjects, whereas S. pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and other organisms were more commonly isolated from pneumonia participants. The drug-resistance rates of S. pneumoniae to penicillin, macrolide and quinolone antibiotics commonly used empirically to treat community acquired pneumonia was 52.6%, 79% and 79% respectively. The sensitivity of Pseudomonas to Carbapenems was 50% and to fluoroquinolones was 16.7% while all the strains were found to be resistant to Aminoglycosides, Penicillin, Cephalosporins, and Macrolides. Conclusions: In our study, we found that K. pneumoniae was the most common pathogen in patients with an exacerbation of COPD while S. pneumoniae was the most common pathogen in patients with community acquired pneumonia. In our study the organisms responsible for community acquired pneumonia were largely resistant to penicillins, macrolides, and tetracyclines, which are the antibiotics of choice for empirical treatment. Similarly, in patients with exacerbation of COPD, the organisms isolated had a far greater degree of resistance to the above-mentioned antibiotics than that seen in our patients with pneumonia. We conclude that antibiotic regimens should be culture driven rather than empirical to be effective while also countering drug resistance.

Introduction. Inflammation in viral-induced acute exacerbations of chronic obstructive pulmonary disease (COPD) is not studied enough.The aim was to establish molecular pattern of inflammation in viral-induced acute exacerbations of chronic obstructive pulmonary disease (AECOPD) in comparison with bacterial AECOPD and to reveal associations with AECOPD phenotype and subsequent COPD progression.Materials and methods. Subjects hospitalized with acute exacerbations of COPD (AECOPD) of which 60 were viral, 60 were bacterial and 60 were viral-bacterial were recruited to single center prospective (52 weeks) cohort study. Control group – 30 healthy people. COPD were diagnosed previously during stable phase of the disease according to spirographic criteria. Viral AECOPD were confirmed by detection of RNA of influenza A and B, respiratory syncytial virus, rhinovirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in sputum or bronchoalveolar lavage fluid (BALF) using reverse transcription-polymerase chain reaction (RT-PCR). Bacterial AECOPD were confirmed by sputum/BALF neutrophilia or elevated blood procalcitonin levels or by detecting bacteria by standard culture method. Plasma concentrations of cytokines, fibrotic markers, enzymes were measured by enzyme-linked immunosorbent assay, plasma fibrinogen – by Clauss method. Complex lung function investigation, Dopplerechocardiography, subsequent AECOPD assessment were done. Kruskal-Wallis and chi-square test were used to compare groups, Cox regression and linear regression – to explore relationships.Results. Viral AECOPD were characterized by highest plasma concentrations of Eosinophilic cationic protein (62,3 (52,4; 71,0) ng/ml)), interleukin-5 (IL-5) (11,3 (8,4; 15,9) pg/ml), fibroblast growth factor-2 (FGF-2) (10,4 (6,2; 14,9) pg/ml), transforming growth factor-β1 (TGF-β1) (922,4 (875,7; 953,8) pg/ml), hyaluronic acid (185,4 (172,8; 196,3) ng/ml), amino-terminal propeptide of type III procollagen (PIIINP) (249,2 (225,1; 263,7) ng/ml), matrix metalloproteinase-1 (MMP-1) (235,2 (208,6; 254,9) pg/ml). Levels of IL-5 during AE COPD was the predictor of FEV1, bronchodilation coefficient, subsequent exacerbations at remote period, fibrinogen was associated with FEV1, PIIINP and FGF-2 with DLco, PaO2, mean pulmonary artery pressure (mPAP), exacerbations, MMP-1 – with mPAP.Conclusions. In virus-induced AECOPD inflammation pattern differed from those in bacterial one and associated with AECOPD phenotype and COPD phenotype at the stable phase.

Objective To investigate the safety of bronchoalveolar lavage (BAL) in the treatment of acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and type Ⅱ respiratory failure patients during mon-invasive positive pressure ventilation (NIPPV). Methods 80 patients with AECOPD combined with type Ⅱ respiratory failure admitted between January 2016 and April 2017 in the Fourth Affiliated Hospital of Harbin Medical University were randomly divided into treatment group and control group, 40 cases in each group.The two groups were given NIPPV on the basis of routine treatment.The treatment group was given BAL at the same time as NIPPV treatment.The blood gas indexes, heart rate, changes in mean arterial pressure, and incidence of adverse reactions were compared between the two groups before given BAL and after 30 min, 1 h, 2 h. Results There was no significant difference in heart rate and mean arterial pressure between the two groups at each time (all P>0.05). Arterial partial pressure of oxygen values in the observation group were significantly higher than those in the control group at each time (all P 0.05). Conclusions The safety of BAL lavage during the NIPPV of patients with AECOPD and type Ⅱ respiratory failure is good, and the improvement of ventilation function is more significant. Key words: Non-invasive positive pressure ventilation; Bronchoalveolar lavage; Acute exacerbation of chronic obstructive pulmonary disease; Type Ⅱ respiratory failure

1. The effect of rapamycin (0.001 to 5 mg kg-1) on the increased leukocyte counts in bronchoalveolar lavage (BAL) fluid and hyperreactivity of isolated bronchial strips to histamine and acetylcholine (ACh) was studied following the intravenous injection of Sephadex beads to guinea-pigs. 2. The intramuscular (i.m.) injection of rapamycin (0.012 to 5 mg kg-1) dose-dependently inhibited the increase in leukocyte counts in BAL fluid. Rapamycin (5 mg kg-1) reduced the numbers of eosinophils neutrophils, macrophages and lymphocytes in BAL fluid by 64, 55, 19 and 50% respectively. In addition, rapamycin (0.012 to 5 mg kg-1) significantly inhibited the Sephadex-induced hyperreactivity of bronchial tissue to both histamine and ACh. 3. At a dose of 0.001 mg kg-1, rapamycin did not significantly reduce leukocyte infiltration or bronchial hyperreactivity. 4. Cyclosporin (5 mg kg-1) significantly reduced both lymphocyte and eosinophil numbers in BAL fluid of Sephadex-injected guinea-pigs whereas dexamethasone (1 mg kg-1) significantly reduced lymphocyte numbers. Neither drug affected the bronchial hyperreactivity to histamine and ACh. 5. It is concluded that the new immunosuppressive drug, rapamycin, is a potent inhibitor of leukocyte migration and bronchial hyperreactivity observed following the intravenous injection of Sephadex beads to guinea-pigs. Rapamycin also appears to be more effective than cyclosporin or dexamethasone in reducing leukocyte counts and bronchial hyperreactivity in this model. 6. Our results suggest that inflammatory mechanisms which are inhibited by rapamycin may be important in the induction of Sephadex-induced hyperreactivity.

Management of chronic obstructive pulmonary disease: Moving beyond the asthma algorithm

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is characterized by heightened inflammation and immune dysregulation, yet its underlying molecular mechanisms remain incompletely understood. This study aimed to identify ferroptosis-associated signature genes in AECOPD and to elucidate their immunological implications. Methods: Differentially expressed ferroptosis-related genes(DEGs) were screened from the GSE112165 dataset (GEO, Gene Expression Omnibus database). Key feature genes were identified using an integrated machine learning and network analysis strategy. External validation was conducted using the GSE22148 dataset, six bronchoalveolar lavage fluid (BALF) samples, and 40 clinical sputum samples. Functional enrichment analysis was performed to delineate relevant biological pathways. Immune and stromal cell infiltration differences were quantified using computational deconvolution frameworks, and their correlations with candidate genes were assessed. Results: Two ferroptosis-related signature genes—SCD(Stearoyl-CoA Desaturase) and FABP4(Fatty Acid Binding Protein 4)—were identified as potential diagnostic markers. Their diagnostic performance was further validated in independent datasets. Among them, FABP4 showed significant downregulation in AECOPD, which was consistently confirmed across BALF and sputum samples. Immune infiltration analysis revealed a strong association between FABP4 expression and neutrophil infiltration. Notably, conventional dendritic cells (cDCs) were significantly reduced in AECOPD patients, suggesting a possible link between ferroptosis and impaired antigen presentation. Conclusions:(1) This study is the first to comprehensively demonstrate that decreased FABP4 expression may enhance ferroptosis susceptibility by disrupting lipid metabolism, thereby modulating immune cell recruitment and function in AECOPD.(2) The marked reduction of cDCs suggests that ferroptosis may contribute to dysregulated antigen presentation in AECOPD. Taken together, these findings offer novel mechanistic insights into the interplay between ferroptosis and immune dysfunction in AECOPD and provide a theoretical foundation for the development of targeted diagnostic and therapeutic strategies.

Актуальность. Саркоидоз относится к воспалительным гранулематозным заболеваниям неизвестной этиологии. Наиболее часто в процесс вовлекаются легкие и внутригрудные лимфоузлы. В связи с необходимостью оценивать течение воспалительного процесса большое значение приобретает вопрос выделения критериев активности заболевания. В клинической практике с этой целью широко используют показатель лимфоцитоза жидкости бронхоальвеолярного лаважа (жБАЛ) и уровень неоптерина крови, однако надежность этих методов для мониторинга текущего воспаления при саркоидозе может оказаться недостаточно высокой. Цель – оценить надежность показателя лимфоцитоза жБАЛ и уровня неоптерина крови в качестве характеристик активности текущего воспалительного процесса у больных саркоидозом органов дыхания. Материал и методы. У 111 больных саркоидозом органов дыхания проводили исследование показателя лимфоцитоза жБАЛ и уровня неоптерина крови. У 39 пациентов была первая рентгенологическая стадия саркоидоза, у 57−вторая, у 15−третья. У 28 пациентов сравнивали уровень лимфоцитов в порциях жБАЛ, взятых из разных сегментов одного легкого. Полученные данные сопоставляли с результатами функциональных исследований, рентгенологической стадией болезни и изменениями легочной паренхимы при компьютерной томографии. Результаты. Показатель лимфоцитоза жБАЛ был связан с уровнем неоптерина плазмы крови (r=0,26, p=0,027), значением форсированной жизненной емкости легких (r=-0,24, p=0,04) и не зависел от рентгенологической стадии болезни. У 43% пациентов выявлялось существенное (от 5 до 23%) различие относительного числа лимфоцитов в порциях жБАЛ, взятых из разных долей одного легкого. У 40% пациентов с признаками активности текущего воспаления значения неоптерина не превышали норму. Заключение. Неравномерность воспалительного процесса в легочной ткани при саркоидозе оказывает существенное влияние на выраженность лимфоцитоза жБАЛ, получаемой из разных отделов легкого. Мониторирование показателя лимфоцитоза жБАЛ и уровня неоптерина плазмы крови не может служить надежным ориентиром для оценки динамики воспалительного процесса при саркоидозе.

&lt;b&gt;Aim: &lt;/b&gt;To evaluate the relationships between sputum and bronchoalveolar lavage (BAL) cellular and bacterial findings and severity of exacerbation of chronic obstructive pulmonary disease (ECOPD).&lt;br /&gt; &lt;b&gt;Patients &amp;amp; methods: &lt;/b&gt;A cross-section study was conducted on 307 patients with ECOPD. They underwent sputum and BAL inflammatory cell count and bacterial culture.&lt;br /&gt; &lt;b&gt;Results:&lt;/b&gt; Patients with severe ECOPD have significantly higher neutrophils percentage (neut.%), lower lymphocytes percentage (lymph.%), lower eosinophils percentage (eosin.%) and higher neutrophil/lymphocyte ratio (NLR) as compared to patients with mild ECOPD. It was also shown that patients with severe ECOPD had significantly higher BAL neut.%, lower lymph.%, lower eosin.%, and higher NLR as compared to the other two subgroups. Also, patients with severe ECOPD have significantly higher frequency of cases with monomicrobial (71.30% vs. 36.10%) and polymicrobial (21.25% vs. 2.10%) growths in comparison to patients with mild ECOPD.&lt;br /&gt; &lt;b&gt;Conclusions: &lt;/b&gt;Cellular and bacterial findings in sputum and BAL are related to severity of ECOPD.

Chronic obstructive pulmonary disease (COPD) is characterised by a progressive pulmonary and systemic inflammation. Acute exacerbations of COPD (AECOPD) are associated with acute inflammation and infection, increase in the rates of morbidity and mortality. Previous proteomic studies have focussed on identifying proteins involved in COPD pathogenesis in samples collected from the lung (e.g. lung tissue biopsies, bronchoalveolar lavage and sputum) but not from blood of patients who experienced AECOPD. In this study, plasma was analysed by two independent quantitative proteomics techniques; isobaric tag for relative and absolute quantitation (iTRAQ) and multiple reaction monitoring (MRM) to identify differential expression of circulating proteins in patients with stable COPD (sCOPD) and AECOPD. Firstly, iTRAQ performed on pooled plasma samples from AECOPD, sCOPD, and healthy non-smoking controls (HC) revealed 15 differentially expressed proteins between the 3 groups. MRM subsequently performed on a separate cohort of AECOPD, sCOPD, and HC patients confirmed 9 proteins to be differentially expressed by AECOPD compared to HC (Afamin, alpha-1-antichymotrypsin, Apolipoprotein E, Beta-2-glycoprotein 1, Complement component C9, Fibronectin, Immunoglobulin lambda like polypeptide 5, Inter-alpha-trypsin inhibitor heavy chain H3, Leucine rich alpha-2-glycoprotein 1). Network analysis demonstrates that most of these proteins are involved in proteolysis regulation, platelet degranulation and cholesterol metabolism. In conclusion, several potential plasma biomarkers for AECOPD were identified in this study. Further validation studies of these proteins may elucidate their roles in the development of AECOPD.

Exacerbation of Bleomycin-Induced Injury and Fibrosis by Pneumonectomy in the Residual Lung of Mice