Risk Factors for Influenza-Induced Exacerbations and Mortality in Non-Cystic Fibrosis Bronchiectasis.

Influenza infection is a cause of exacerbations in patients with chronic pulmonary diseases. The aim of this study was to investigate the clinical outcomes and identify risk factors associated with hospitalization and mortality following influenza infection in adult patients with bronchiectasis. Using the Chang Gung Research Database, we identified patients with bronchiectasis and influenza-related infection (ICD-9-CM 487 and anti-viral medicine) between 2008 and 2017. The main outcomes were influenza-related hospitalization and in-hospital mortality rate. Eight hundred sixty-five patients with bronchiectasis and influenza infection were identified. Five hundred thirty-six (62%) patients with bronchiectasis were hospitalized for influenza-related infection and 118 (22%) patients had respiratory failure. Compared to the group only seen in clinic, the hospitalization group was older, with more male patients, a lower FEV1, higher bronchiectasis aetiology comorbidity index (BACI), and more acute exacerbations in the previous year. Co-infections were evident in 55.6% of hospitalized patients, mainly caused by Pseudomonas aeruginosa (15%), fungus (7%), and Klebsiella pneumoniae (6%). The respiratory failure group developed acute kidney injury (36% vs. 16%; p < 0.001), and shock (47% vs. 6%; p < 0.001) more often than influenza patients without respiratory failure. The overall mortality rate was 10.8% and the respiratory failure group exhibited significantly higher in-hospital mortality rates (27.1% vs. 6.2%; p < 0.001). Age, BACI, and previous exacerbations were independently associated with influenza-related hospitalization. Age, presence of shock, and low platelet counts were associated with increased hospital mortality. Influenza virus caused severe exacerbation in bronchiectasis, especially in those who were older and who had high BACI scores and previous exacerbations. A high risk of respiratory failure and mortality were observed in influenza-related hospitalization in bronchiectasis. We highlight the importance of preventing or treating influenza infection in bronchiectasis.

Increased Interleukin-17 and Glucocorticoid Receptor-ß Expression in Interstitial Lung Diseases and Corticosteroid Insensitivity.

Background: Treatment responsiveness to corticosteroids is excellent for cryptogenic organizing pneumonia (COP) and sarcoidosis, but suboptimal for idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP). We hypothesise that the differential expression of IL-17 contributes to variable corticosteroid sensitivity in different interstitial lung diseases. Objective: To determine the associations among expression of IL-17, glucocorticoid receptor-ß and responsiveness to corticosteroid treatment in interstitial lung diseases. Methods: Immunohistochemical (IHC) staining was performed on formalin-fixed paraffin-embedded (FFPE) lung tissues obtained by bronchoscopic, CT-guided or surgical biopsies, and quantified by both cell counting (% positive cells) by individuals and by software IHC Profiler plugin of ImageJ (opacity density score). We studied the effect of IL-17 on corticosteroid sensitivity in human fibroblast MRC5 cell line. Results: Compared with specimens from patients with COP (n =13) and sarcoidosis (n =13), those from IPF patients (n = 21) had greater GR-ß and IL-17 expression and neutrophil infiltration. Radiographic progression after oral corticosteroid treatment was positively correlated with the expression in IL-17 and GR-ß/GR-α ratio in all patients (COP, sarcoidosis and IPF) and also within the IPF subgroup only. IL-17 expression level was positively associated with GR-ß and GR-ß/GR-α ratio. In MRC5 cells, exogenous IL-17 increased the production of collagen I and up-regulated GR-ß expression and dexamethasone's suppressive effect on collagen I production was impaired by IL-17, and silencing IL-17 receptor A gene attenuated the effect of IL-17. Conclusion: Up-regulation of GR-ß/GR-α ratio by IL-17 could be associated with the relative corticosteroid-insensitivity of IPF.

Oxygen Desaturation Is Associated With Fibrocyte Activation via Epidermal Growth Factor Receptor/Hypoxia-Inducible Factor-1α Axis in Chronic Obstructive Pulmonary Disease.

Fibrocytes are bloodborne mesenchymal progenitors which accumulate and differentiate at the disease site. We investigated whether hypoxemia activates fibrocytes, accelerating airflow limitation and exercise intolerance in chronic obstructive pulmonary disease (COPD) patients. Flow cytometry was used to determine collagen I+/CD45+ fibrocytes and α-smooth muscle actin+ differentiating fibrocytes within peripheral blood and cultured cells, as well as the expression of CXC chemokine receptor 4 (CXCR4), epidermal growth factor receptor (EGFR), connective tissue growth factor (CTGF) and hypoxia-inducible factor (HIF)-1α. Fibrocytes in lung specimens were identified by confocal microscopy. Compared to non-desaturators, COPD desaturators (peripheral blood oxygen saturation ≤88% during exercise) had greater number of fibrocytes in peripheral blood and lung specimens, paralleled with faster yearly lung function decline and a 6-minute walk distance. Fibrocytes from desaturators expressed more EGFR, CXCR4, CTGF, and HIF-1α, with a higher capacity of proliferation and myofibroblastic differentiation. Hypoxia (5% oxygen) increased the expression of EGFR, CXCR4, CTGF, and HIF-1α, the number and differentiation in fibrocytes. These effects were attenuated by EGFR inhibitor gefitinib, HIF-1α gene silencing, and anti-CTGF antibody. These data elucidate that hypoxemia triggers fibrocyte activation through the EGFR/HIF-1α axis, aggravating airflow obstruction in COPD.

Emphysema-Predominant COPD Had a Greater 5-Year Mortality and a Worse Annual Decline in Lung Function Than Airway Obstruction-Predominant COPD or Asthma at Initial Same Degree of Airflow Obstruction.

Background and Objectives: We studied whether the extent of exertional oxygen desaturation and emphysema could cause greater mortality in COPD and asthma independent of airflow obstruction. Materials and Methods: We performed a 5-year longitudinal observational study in COPD and asthma patients who matched for airflow obstruction severity. All subjects performed a 6-min walk test (6MWT) and high-resolution computed tomography (HRCT) and followed spirometry and oxygen saturation (SpO2) during the 6MWT every 3-6 months. Overall survival was recorded. Cumulative survival curves were performed according to the Kaplan-Meier method and compared with the log-rank test. Results: The COPD group had higher emphysema scores, higher Δinspiratory capacities (ICs) and lower SpO2 during the 6MWT, which showed a greater yearly decline in FEV1 (40.6 mL) and forced vital capacity (FVC) (28 mL) than the asthma group (FEV1, 9.6 mL; FVC, 1.2 mL; p < 0.05). The emphysema-predominant COPD group had an accelerated annual decline in lung function and worse survival. The nadir SpO2 ≤ 80% and a higher emphysema score were the strong risk factors for mortality in COPD patients. Conclusions: The greater structural changes with a higher emphysema score and greater desaturation during the 6MWT in COPD may contribute to worse yearly decline in FEV1 and higher five-year mortality than in asthma patients with a similar airflow obstruction. The lowest SpO2 ≤ 80% during the 6MWT and emphysema-predominant COPD were the strong independent factors for mortality in chronic obstructive airway disease patients.

Increased Th1 Cells with Disease Resolution of Active Pulmonary Tuberculosis in Non-Atopic Patients.

Type 1 CD4+ T helper (Th1) cells mediate resistance to Mycobacterium tuberculosis (Mtb), and Th2 immunity generates specific immunoglobulin E upon allergen exposure. We investigated the impact of active tuberculosis (TB), atopic status, and anti-TB treatment on the balance between Th1 and Th2 (type 2 CD4+ T helper) immunity. CD4+/interferon (IFN)-γ+ Th1 cells (%Th1) and CD4+/interleukin-4+ Th2 cells (%Th2) in bronchoalveolar lavage (BAL) fluid and peripheral blood mononuclear cells (PBMCs) were measured by flow cytometry. The BAL %Th1 was higher in TB patients at baseline, compared to that in non-TB subjects, and was further increased in TB patients after stimulation with phorbol myristate acetate and ionomycin. The stimulated BAL %Th1 was inversely correlated with the severity score of chest radiography in TB patients. Heat-killed Mtb triggered more IFN-γ and nitrite production, as determined by enzyme-linked immunosorbent assay and the Griess reaction, respectively, from the alveolar macrophages of TB patients than that of non-TB subjects. Non-atopic TB participants had a higher %Th1 in PBMCs, compared to atopic individuals, and their %Th1 decreased after 3-month anti-TB treatment. Th1 response is provoked by active TB infection, is associated with less severe radiographic changes, is reduced in atopic patients with active TB infection, and is attenuated after anti-TB treatment.

Short-Chained Platinum Complex Catalyzed Hydrosilylation under Thermomorphic Conditions: Heterogeneous Phase Separation at Ice Temperature.

Homogeneous catalysts PtCl2[5,5'-bis-(n-ClCF2(CF2)3CH2OCH2)-2,2'-bpy] (2A) and PtCl2[5,5'-bis-(n-HCF2(CF2)3CH2OCH2)-2,2'-bpy] (2B), which contained short fluorous chains, were synthesized and used in catalysis of hydrosilylation of alkynes. In these reactions the thermomorphic mode was effectively used to recover these catalysts from the reaction mixture up to eight cycles by taking advantage of heterogeneous phase separation at ice temperature. This kind of catalysis had previously been observed in fluorous catalysts of platinum containing about 50% F-content, but in this work the percentage of F-content is decreased to only about 30%, by which we termed them as "very light fluorous". Our new type of catalyst with limited number of F-content is considered as the important discovery in the fluorous technology field as the reduced number of fluorine atoms will help to be able to comply the EPA 8-carbon rule. The metal leaching after the reaction has been examined by ICP-MS, and the testing results show the leaching of residual metal to be minimal. Additionally, comparing these results to our previous work, fluorous chain assisted selectivity has been observed when different fluorous chain lengths of the catalysts are used. It has been found that there exists fluorous chain assisted better selectivity towards ß-(E) form in the Pt-catalyzed hydrosilylation of non-symmetric terminal alkyne when the Pt catalyst contains short fluorous chain (i.e., 4 Cs). Phenyl acetylenes showed the opposite regioselectivity due to pi-pi interaction while using the same catalyst via Markovnikov's addition to form terminal vinyl silane, which is then a major product for Pt-catalyzed hydrosilylation of terminal aryl acetylene with triethylsilane. Finally, the kinetic studies indicate that the insertion of alkyne into the Pt-H bond is the rate-determining step.

Etiology and characteristics of patients with bronchiectasis in Taiwan: a cohort study from 2002 to 2016.

BACKGROUND: Bronchiectasis is a chronic infectious respiratory disease with diverse causes and ethnic or geographic differences. However, few large-scale studies of its etiology have been conducted in Asia. This study aimed to determine the etiology and clinical features of bronchiectasis in Taiwan. METHODS: This longitudinal cohort study investigated the etiology and clinical features of newly diagnosed non-cystic fibrosis bronchiectasis patients from January 2002 to December 2016. The clinical, functional and microbiological data of patients were retrieved from the Chang Gung Research Database, which includes seven medical facilities throughout Taiwan. The index date was the date of the first bronchiectasis diagnosis. Known diseases that were diagnosed before the index date were regarded as etiologies of bronchiectasis. RESULTS: The cohort comprised 15,729 adult patients with bronchiectasis. Idiopathic (32%) was the most common cause, followed by post-pneumonia (24%). Other causes included post-tuberculosis (12%), chronic obstructive pulmonary disease (14%), asthma (10%), gastroesophageal reflux disease (2%) and rheumatic diseases (2%). At diagnosis, 8487 patients had sputum culture. Pseudomonas aeruginosa (5.3%) was the most common bacteria, followed by non-tuberculosis mycobacteria (3.6%), Haemophilus influenzae (3.4%) and Klebsiella pneumoniae (3.1%), but 6155 (72.1%) had negative sputum cultures. Patients with post-tuberculosis had a higher sputum isolation rate of non-tuberculosis mycobacteria than P. aeruginosa. Patients with post-tuberculosis and post-pneumonia bronchiectasis had a higher frequency of chronic lung infection than other groups (p < 0.05). Clinical characteristics, such as gender, lung function, comorbidities and microbiology, were significantly different between idiopathic and known etiologies. CONCLUSIONS: Idiopathic, post-infection and tuberculosis constitute major bronchiectasis etiologies in Taiwan. Clinical characteristics and sputum microbiology were distinct among separate etiology phenotypes.

Structure-Dependent Photoluminescence in Low-Dimensional Ethylammonium, Propylammonium, and Butylammonium Lead Iodide Perovskites.

Hybrid organic-inorganic perovskites have attracted great attention as the next generation materials for photovoltaic and light-emitting devices. However, their environment instability issue remains as the largest challenge for practical applications. Recently emerging two-dimensional (2D) perovskites with Ruddlesden-Popper structures are found to greatly improve the stability and aging problems. Furthermore, strong confinement of excitons in these natural quantum-well structures results in the distinct and narrow light emission in the visible spectral range, enabling the development of spectrally tunable light sources. Besides the strong quasi-monochromatic emission, some 2D perovskites composed of the specific organic cations and inorganic layer structures emit a pronounced broadband emission. Herein, we report the light-emitting properties and the degradation of low-dimensional perovskites consisting of the three shortest alkylammonium spacers, mono-ethylammonium (EA), n-propylammonium (PA), and n-butylammonium (BA). While (BA)2PbI4 is known to form well-oriented 2D thin films consisting of layers of corner-sharing PbI6 octahedra separated by a bilayer of BA cations, EA with shorter alkyl chains tends to form other types of lower-dimensional structures. Nevertheless, optical absorption edges of as-prepared fresh EAPbI3, (PA)2PbI4, and (BA)2PbI4 are obviously blue-shifted to 2.4-2.5 eV compared to their 3D counterpart, methylammonium lead iodide (MAPbI3) perovskite, and they all emit narrow excitonic photoluminescence. Furthermore, by carefully optimizing deposition conditions, we have achieved a predominantly 2D structure for (PA)2PbI4. However, unlike (BA)2PbI4, upon exposure to ambient environment, (PA)2PbI4 readily transforms to a different crystal structure, exhibiting a prominently broadband light from ∼500 to 800 nm and a gradual increase in intensity as structural transformation proceeds.

Increased Ratio of Matrix Metalloproteinase-9 (MMP-9)/Tissue Inhibitor Metalloproteinase-1 from Alveolar Macrophages in Chronic Asthma with a Fast Decline in FEV1 at 5-Year Follow-up.

Chronic asthma is associated with progressive airway remodeling, which may contribute to declining lung function. An increase in matrix metalloproteinases-9 (MMP-9)/tissue inhibitor metalloproteinase-1 (TIMP-1) may indicate airway inflammation and bronchial injury. Bronchial biopsy specimens and alveolar macrophages (AMs) were obtained from patients with asthma under regular treatment with inhaled corticosteroids or combination therapy and normal subjects (n = 10). Asthmatics included those with a slow forced expiratory volume in one second (FEV1) decline (<30 mL/year, n = 13) and those with a fast FEV1 decline (≥30 mL/year, n = 8) in 5-year follow-up. Immunostaining expression of MMP-9 and TIMP-1 was detected in airway tissues. MMP-9 and TIMP-1 was measured from AMs cultured for 24 h. After the 5-year treatment, the methacholine airway hyperresponsiveness of the slow FEV1 decline group was decreased, but that of the fast FEV1 decline group was increased (PC20, provocative concentration causing a 20% decrease in FEV1, 3.12 ± 1.10 to 1.14 ± 0.34 mg/dL, p < 0.05). AMs of asthma with a fast FEV1 decline released a higher level of MMP-9 (8.52 ± 3.53 pg/mL, p < 0.05) than those of a slow FEV1 decline (0.99 ± 0.20 pg/mL). The MMP-9/TIMP ratio in the fast FEV1 decline group (0.089 ± 0.032) was higher than that of the slow FEV1 decline group (0.007 ± 0.001, p < 0.01). The annual FEV1 decline in 5 years was proportional to the level of MMP-9 (r = 57, p < 0.01) and MMP-9/TIMP-1 ratio (r = 0.58, p < 0.01). The airways of asthma with greater yearly decline in FEV1 showed an increased thickness of submucosa and strong expression of MMP-9. An increase in MMP-9 and MMP-9/TIMP-1 in airways or AMs could be indicators of chronic airway inflammation and contribute to a greater decline in lung function of patients with chronic asthma.

Maintenance Negative Pressure Ventilation Improves Survival in COPD Patients with Exercise Desaturation.

Negative pressure ventilation (NPV), when used as an adjuvant to pulmonary rehabilitation, improves lung function, increases exercise capacity, and reduces exacerbations. The aim of this study was to determine whether maintenance NPV improves long-term clinical outcomes and reduces mortality in patients with chronic obstructive pulmonary disease (COPD). Between 2003 and 2009, 341 patients were treated for COPD either with or without hospital-based NPV. We measured forced expiratory volume in one second (FEV1), 6-min walking distance (6MWD), and oxygen saturation by pulse oximetry (SpO2) during a 6-min walk test (6MWT) every 3-6 months. Desaturation (D) during the 6MWT was defined as a reduction in SpO2 of ≥10% from baseline. The NPV group had a better survival outcome than the Non-NPV group. The 8-year survival probabilities for the NPV and Non-NPV groups were 60% and 20%, respectively (p < 0.01). Baseline desaturation was a significant risk factor for death, and the risk of death increased with desaturation severity (SpO2 80~89: hazard ratios (HR) 2.7, 95% confidence interval (CI) 1.4-5.3; SpO2 < 80: HR 3.1, 95% CI 1.3-7.4). The NPV group had a slower decline in lung function and 6MWD. The NPV + D and Non-NPV+D had a threefold and fourfold increase in the risks of all-cause mortality compared with the NPV-ND, respectively. Maintenance non-invasive NPV reduced long-term mortality in COPD patients. The desaturating COPD patients had an increased mortality risk compared with non-desaturating COPD patients.

Oxygen desaturation during the 6-min walk test as a risk for osteoporosis in non-cystic fibrosis bronchiectasis.

BACKGROUND: Osteoporosis is a common comorbidity in non-cystic fibrosis (non-CF) bronchiectasis patients. We determined whether desaturation during 6-min walk test (6MWT) can be a predictor for osteoporosis risk. METHODS: This was a retrospective cross-sectional study. Sixty-six non-CF bronchiectasis patients were enrolled. Lung function, walking distance, the lowest oxygen saturation (SpO2), the fall in SpO2 (ΔSpO2), and the distance-saturation product (DSP) were determined during the 6MWT. Desaturators (n = 45) were defined as those with ΔSpO2 > 10% or the lowest SpO2 < 88%. Bone mineral density (BMD) was determined through dual-energy X-ray absorptiometry. The severity of non-CF bronchiectasis was evaluated using high-resolution computed tomography. RESULTS: Osteoporosis was evident in more desaturators (82%) than non-desaturators (43%, p < 0.01). BMD at the level of the femoral neck was significantly lower in desaturators than in non-desaturators (- 3.6 ± 1.1 vs. - 2.4 ± 0.9, p < 0.01). BMD was correlated positively with the lowest SpO2 and negatively with ΔSpO2 and severe exacerbations. In multivariate linear regression analysis, desaturation during 6MWT was the most significant predictive factor for osteoporosis (95% confidence interval - 1.60 to - 0.26, p = 0.01). Other risk factors included old age, low body mass index and severe exacerbation. CONCLUSIONS: Exertional desaturation during the 6MWT was a significant predictive factor for osteoporosis in Asian non-CF bronchiectasis patients. The 6MWT may be useful in identifying the osteoporotic phenotype of non-CF bronchiectasis and increasing clinician awareness to promote early intervention.

Mesalazine-related lung disease in a patient with ulcerative colitis: A case report.

RATIONALE: Mesalazine is widely used to treat inflammatory bowel disease (IBD). However, discriminating between pulmonary manifestations of IBD and drug-related lung disease remains a challenge. There were few case reports of mesalazine-related organizing pneumonia so far. PATIENT CONCERNS: A 75-year-old female was diagnosed with ulcerative colitis and took mesalazine over a period of 2 years and 8 months. She presented with progressive shortness of breath for 3 days and visited our emergency department. Chest radiography showed increased bilateral infiltrates. During hospitalization her clinical condition deteriorated, and she was transferred to our intensive care unit under noninvasive ventilator support. DIAGNOSIS: Computed tomography (CT) scan showed diffuse peribronchial and subpleural consolidations in bilateral lungs. Possible etiologies of interstitial lung disease were surveyed, including various infectious diseases and connective tissue diseases. Transbronchial lung biopsy showed characteristic features of organizing pneumonia. INTERVENTIONS: Under the consideration of mesalazine-related lung disease, mesalazine was discontinued early in disease course and steroid therapy was given. OUTCOMES: The patient was discharged from hospital with improved clinical symptoms and radiographic images. LESSONS: Although this patient suffered a life-threatening adverse event, prompt diagnosis with proper management can result in a favorable outcome.

Efficient Defect Healing of Transition Metal Dichalcogenides by Metallophthalocyanine.

Two-dimensional (2D) transition metal dichalcogenides (TMDCs) have attracted great attention as alternatives to graphene with semiconducting band gaps. Mono- or few-layer TMDCs can be prepared by various methods, but regardless of the fabrication methods [such as mechanical exfoliation and chemical vapor deposition (CVD)], TMDCs contain many structural defects, which significantly affect their physical properties and limit their performance in applications. Metallophthalocyanines (MPcs) are organic semiconductors, and as dopants, they are capable of modulating the optical and electrical properties of other semiconducting materials. Here, we report that besides the ability to modulate the optoelectronic properties of 2D TMDCs, MPc molecules can be used to heal defects and improve the physicochemical properties of TMDCs. Doping of planar MPc molecules to TMDCs is achieved by a simple solution dip-coating method and results in a significant improvement in the optical properties and thermal responses of CVD-grown TMDCs, even comparable to those of mechanically exfoliated counterparts. Study of carrier dynamics shows that the adsorption of MPc on the TMDC surface leads to the complete suppression of the mid-gap defect-induced absorption in TMDCs. Furthermore, MPc molecules with a large lateral size are found to effectively reduce the point defects in mechanically exfoliated TMDCs introduced during the preparation process. Our results not only clarify the optoelectronic modulation mechanism of chemical doping but also offer a simple method to control the nanosized defects in 2D TMDCs.

Nintedanib reduces ventilation-augmented bleomycin-induced epithelial-mesenchymal transition and lung fibrosis through suppression of the Src pathway.

Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can increase lung inflammation and pulmonary fibrogenesis. Src is crucial in mediating the transforming growth factor (TGF)-ß1-induced epithelial-mesenchymal transition (EMT) during the fibroproliferative phase of ARDS. Nintedanib, a multitargeted tyrosine kinase inhibitor that directly blocks Src, has been approved for the treatment of idiopathic pulmonary fibrosis. The mechanisms regulating interactions among MV, EMT and Src remain unclear. In this study, we suggested hypothesized that nintedanib can suppress MV-augmented bleomycin-induced EMT and pulmonary fibrosis by inhibiting the Src pathway. Five days after administrating bleomycin to mimic acute lung injury (ALI), C57BL/6 mice, either wild-type or Src-deficient were exposed to low tidal volume (VT ) (6 ml/kg) or high VT (30 ml/kg) MV with room air for 5 hrs. Oral nintedanib was administered once daily in doses of 30, 60 and 100 mg/kg for 5 days before MV. Non-ventilated mice were used as control groups. Following bleomycin exposure in wild-type mice, high VT MV induced substantial increases in microvascular permeability, TGF-ß1, malondialdehyde, Masson's trichrome staining, collagen 1a1 gene expression, EMT (identified by colocalization of increased staining of α-smooth muscle actin and decreased staining of E-cadherin) and alveolar epithelial apoptosis (P < 0.05). Oral nintedanib, which simulated genetic downregulation of Src signalling using Src-deficient mice, dampened the MV-augmented profibrotic mediators, EMT profile, epithelial apoptotic cell death and pathologic fibrotic scores (P < 0.05). Our data indicate that nintedanib reduces high VT MV-augmented EMT and pulmonary fibrosis after bleomycin-induced ALI, partly by inhibiting the Src pathway.

Trichostatin A attenuates ventilation-augmented epithelial-mesenchymal transition in mice with bleomycin-induced acute lung injury by suppressing the Akt pathway.

BACKGROUND: Mechanical ventilation (MV) used in patients with acute respiratory distress syndrome (ARDS) can cause diffuse lung inflammation, an effect termed ventilator-induced lung injury, which may produce profound pulmonary fibrogenesis. Histone deacetylases (HDACs) and serine/threonine kinase/protein kinase B (Akt) are crucial in modulating the epithelial-mesenchymal transition (EMT) during the reparative phase of ARDS; however, the mechanisms regulating the interactions among MV, EMT, HDACs, and Akt remain unclear. We hypothesized that trichostatin A (TSA), a HDAC inhibitor, can reduce MV-augmented bleomycin-induced EMT by inhibiting the HDAC4 and Akt pathways. METHODS: Five days after bleomycin treatment to mimic acute lung injury (ALI), wild-type or Akt-deficient C57BL/6 mice were exposed to low-tidal-volume (low-VT, 6 mL/kg) or high-VT (30 mL/kg) MV with room air for 5 h after receiving 2 mg/kg TSA. Nonventilated mice were examined as controls. RESULTS: Following bleomycin exposure in wild-type mice, high-VT MV induced substantial increases in microvascular leaks; matrix metalloproteinase-9 (MMP-9) and plasminogen activator inhibitor-1 proteins; free radical production; Masson's trichrome staining; fibronectin, MMP-9, and collagen 1a1 gene expression; EMT (identified by increased localized staining of α-smooth muscle actin and decreased staining of E-cadherin); total HDAC activity; and HDAC4 and Akt activation (P < 0.05). In Akt-deficient mice, the MV-augmented lung inflammation, profibrotic mediators, EMT profiles, Akt activation, and pathological fibrotic scores were reduced and pharmacologic inhibition of HDAC4 expression was triggered by TSA (P < 0.05). CONCLUSIONS: Our data indicate that TSA treatment attenuates high-VT MV-augmented EMT after bleomycin-induced ALI, in part by inhibiting the HDAC4 and Akt pathways.

Activation of Src-dependent Smad3 signaling mediates the neutrophilic inflammation and oxidative stress in hyperoxia-augmented ventilator-induced lung injury.

BACKGROUND: Mechanical ventilation and concomitant administration of hyperoxia in patients with acute respiratory distress syndrome can damage the alveolar epithelial and capillary endothelial barrier by producing inflammatory cytokines and reactive oxygen species. The Src tyrosine kinase and Smad3 are crucial inflammatory regulators used for ventilator-induced lung injury (VILI). The mechanisms regulating interactions between high-tidal-volume mechanical ventilation, hyperoxia, and acute lung injury (ALI) are unclear. We hypothesized that high-tidal-volume mechanical stretches and hyperoxia augment lung inflammation through upregulation of the Src and Smad3 pathways. METHODS: Wild-type or Src-deficient C57BL/6 mice, aged between 6 and 8 weeks, were exposed to high-tidal-volume (30 mL/kg) ventilation with room air or hyperoxia for 1-4 h after 2-mg/kg Smad3 inhibitor (SIS3) administration. Nonventilated mice were used as control subjects. RESULTS: We observed that the addition of hyperoxia to high-tidal-volume mechanical ventilation further induced microvascular permeability, neutrophil infiltration, macrophage inflammatory protein-2 and matrix metalloproteinase-9 (MMP-9) production, malondialdehyde, nicotinamide adenine dinucleotide phosphate oxidase activity, MMP-9 mRNA expression, hypoxemia, and Src and Smad3 activation (P < 0.05). Hyperoxia-induced augmentation of VILI was attenuated in Src-deficient mice and mice with pharmacological inhibition of Smad3 activity by SIS3 (P < 0.05). Mechanical ventilation of Src-deficient mice with hyperoxia further reduced the activation of Smad3. CONCLUSIONS: Our data suggest that hyperoxia-increased high-tidal-volume ventilation-induced ALI partially depends on the Src and Smad3 pathways.