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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.jtcvs.2010.02.019 Byline: Shu-Min Lin, Yung-Lun Ni, Chih-Hsia Kuo, Ting-Yu Lin, Tsai-Yu Wang, Fu-Tsai Chung, Han-Pin Kuo Abbreviations: AFB, acid-fast bacillus; AMTD, Amplified Mycobacterium Tuberculosis Direct; BAL, bronchoalveolar lavage; BALF, bronchoalveolar lavage fluid; CI, confidence intervals; CT, computed tomography; EBUS, endobronchial ultrasonography; NAATs, nucleic acid amplification tests; OR, odds ratios; PCR, polymerase chain reaction; TB, tuberculosis Abstract: Our objective was to determine the contribution of endobronchial ultrasound in the diagnostic yields of acid-fast bacillus smear, nucleic acid amplification tests, and culture in bronchoalveolar lavage fluid for pulmonary tuberculosis. Author Affiliation: Department of Thoracic Medicine, Chang Gung Memorial Hospital, Chang Gung University, School of Medicine, Taipei, Taiwan Article History: Received 19 August 2009; Revised 22 November 2009; Accepted 9 February 2010 Article Note: (footnote) This project is supported by NSC 97-2314-B-182A-088-MY3, National Science Council, Taiwan, Republic of China., Disclosures: None

Study objectives: To assess the effect of ribavirin-induced anemia on the outcome of severe acute respiratory syndrome (SARS). Design: A retrospective observational study. Setting: Two medical centers in Taiwan. Patients: [...]

Mesenchymal stem cells (MSCs) are widely considered for treatment of pulmonary fibrosis based on the anti‐inflammatory, antifibrotic, antiapoptotic, and regenerative properties of the cells. Recently, elevated levels of oncostatin M (OSM) have been reported in the bronchoalveolar lavage fluid of a pulmonary fibrosis animal model and in patients. In this work, we aimed to prolong engrafted MSC survival and to enhance the effectiveness of pulmonary fibrosis transplantation therapy by using OSM‐preconditioned MSCs. OSM‐preconditioned MSCs were shown to overexpress type 2 OSM receptor (gp130/OSMRβ) and exhibited high susceptibility to OSM, resulting in upregulation of the paracrine factor, hepatocyte growth factor (HGF). Moreover, OSM‐preconditioned MSCs enhanced cell proliferation and migration, attenuated transforming growth factor‐β1‐ or OSM‐induced extracellular matrix production in MRC‐5 fibroblasts through paracrine effects. In bleomycin‐induced lung fibrotic mice, transplantation of OSM‐preconditioned MSCs significantly improved pulmonary respiratory functions and downregulated expression of inflammatory factors and fibrotic factors in the lung tissues. Histopathologic examination indicated remarkable amelioration of the lung fibrosis. LacZ‐tagged MSCs were detected in the lung tissues of the OSM‐preconditioned MSC‐treated mice 18 days after post‐transplantation. Taken together, our data further demonstrated that HGF upregulation played an important role in mediating the therapeutic effects of transplanted OSM‐preconditioned MSCs in alleviating lung fibrosis in the mice. StemCellsTranslationalMedicine2017;6:1006–1017

Although high-affinity immunoglobulin (Ig)E receptor (FcεRI) expression is upregulated in type 2 (T2)-high asthmatic airway epithelium, its functional role in airway epithelial dysfunction has not been elucidated. Here we report the upregulated expression of FcεRI and p-EGFR (Epidermal Growth Factor Receptor), associated with decreased expression of E-cadherin and claudin-18 in bronchial biopsies of severe T2-high asthmatics compared to mild allergic asthmatics and non-T2 asthmatics. Monomeric IgE (mIgE) decreased the expression of junction proteins, E-cadherin, claudin-18, and ZO-1, and increased alarmin messenger RNA and protein expression in cultured primary bronchial epithelial cells from T2-high asthmatics. Epithelial FcεRI ligation with mIgE decreased transepithelial electric resistance in air-liquid interface cultured epithelial cells. FcεRI ligation with mIgE or IgE- Dinitrophenyl or serum of high-level allergen-specific IgE activated EGFR and Akt via activation of Src family kinases, mediating alarmin expression, junctional protein loss, and increased epithelial permeability. Furthermore, tracheal instillation of mIgE in house dust mite-sensitized mice induced airway hyper-responsiveness, junction protein loss, epithelial cell shedding, and increased epithelial permeability. Thus, our results suggest that IgE-FcεRI cross-linking in the airway epithelium is a potential and unnoticed mechanism for impaired barrier function, increased mucosal permeability, and EGFR-mediated alarmin production in T2-high asthma.

Mechanical ventilators are commonly used to support critically ill patients; however, inappropriate ventilator settings might initiate or augment lung injury. To determine whether a large tidal volume (Vt) augments inflammatory responses and neutrophil sequestration in the lungs of rats receiving intratracheal lipopolysaccharides (LPS). Rats received intratracheal instillation of LPS (0.5 mg/kg) followed by 4 h of mechanical ventilation (MV) at 60 strokes per min with a Vt of 10 mL/kg as control MV, or 30 strokes per min with a Vt of 20 mL/kg of body weight as high-volume MV (HMV). In addition, monoclonal antibodies against rat intercellular adhesion molecule 1 (ICAM-1) or immunoglobulin G (50 mg/kg) were administered 30 min before LPS instillation and MV. Our study demonstrates that HMV enhances pulmonary permeability and induces neutrophil recruitment into the alveolar space and pulmonary edema. Intratracheal instillation of LPS caused marked lung injury, neutrophil recruitment, and production of cytokines and chemokines. Combining LPS instillation and HMV synergistically upregulated interleukin 1 (IL-1) production and neutrophil sequestration in lung tissues. The ICAM-1 expression in lung tissues was responsible for the synergistic effects of neutrophil sequestration. Synergistic upregulation of IL-1 production and neutrophil sequestration was attenuated by blocking ICAM-1 by neutralizing antibody pretreatment. High Vt MV in LPS-injured lung causes synergistic production of IL-1 and sequestration of neutrophil via ICAM-1-dependent effects.

We evaluated whether a goal-directed protocol, without measurement of central venous oxygen saturation, would improve survival in medical intensive care unit (ICU) patients with septic shock. This is a prospective, controlled study in a 24-bed medical ICU at a tertiary care hospital. From a total of 241 consecutive patients with septic shock, 224 were randomly assigned to receive therapy with or without a written protocol using central venous pressure, mean arterial pressure, and urine output as therapeutic goals. Baseline characteristics were similar between groups. Implementation of goal-directed therapy caused a more rapid reversal of persistent shock (47 ± 22.8 vs. 65.4 ± 32.1 h, P= 0.006) and decreases of ICU (50% vs. 67.2%, P= 0.009) and in-hospital (53.7% vs. 71.6%, P= 0.006) mortality rates compared with non-goal-directed therapy. Patients receiving goal-directed therapy also had less risk for developing central nervous system or renal failure than patients without. Patients with goal-directed therapy received more fluid during the period of persistent shock (136.2 ± 119 vs. 88.6 ± 57.7 mL h−1, P= 0.034) and less delay in vasopressor administration (78 ± 22.2 vs. 104.4 ± 29 min, P= 0.001) than patients with non-goal therapy. Implementation of a goal-directed protocol improves survival and clinical outcomes in ICU patients with septic shock. These benefits may arise from adequate fluid resuscitation, earlier vasopressor administration, rapid shock reversal, and protection of major organ function. With central venous oxygen saturation measurement to detect tissue perfusion, the clinical outcomes may be further improved.

There are increased numbers of circulating CD34+progenitor cells for eosinophils in patients with atopic asthma, with a further increase following allergen exposure or spontaneous worsening of asthma. We investigated the expression of IL‐5 and IL‐5Rα receptor in circulating CD34+progenitor cells in allergic asthmatics and the effects of corticosteroids.Using double‐staining techniques, up to 50% of CD34+cells expressed intracellular IL‐5, and by RT – PCR, there was significant expression of IL‐5 mRNA. When cultured in a semi‐liquid methylcellulose medium, there were more eosinophil colony‐forming units grown from asthmatic non‐adherent mononuclear cell depleted of T cells in the presence of the growth factors GM‐CSF, SCF and IL‐3, but not of IL‐5.An anti‐IL‐5Rα receptor antibody and an anti‐sense IL‐5 oligonucleotide reduced the number of eosinophil colony forming units. No IL‐5 mRNA or protein expression on T cells was observed in asthmatics or normal subjects. In the presence of growth factors including IL‐5, there were significantly greater colony numbers with eosinophilic lineage grown from either asthmatics or normal subjects.Dexamethasone (10−6M) suppressed IL‐5 mRNA and protein expression in CD34+cells, and reduced eosinophil colony‐forming units in asthmatics, but not in normal subjects. Dexamethasone did not change the expression of IL‐5Rα on CD34+cells.We conclude that there is increased expression of IL‐5 on blood CD34+cells of patients with asthma and that this expression may auto‐regulate eosinophilic colony formation from these progenitor cells. Corticosteroids inhibit the expression of IL‐5 in circulating CD34+progenitor cells.

This study investigated the role of protein kinase C (PKC) and transcription factor nuclear factor‐κB (NF‐κB) in cyclooxygenase‐2 (COX‐2) expression caused by lipoteichoic acid (LTA), a cell wall component of the gram‐positive bacterium Staphylococcus aureus, in human pulmonary epithelial cell line (A549).LTA caused dose‐ and time‐dependent increases in COX‐2 expression and COX activity, and a dose‐dependent increase in PGE2release in A549 cells. The LTA‐induced increases in COX‐2 expression and COX activity were markedly inhibited by dexamethasone, actinomycin D or cyclohexamide, but not by polymyxin B, which binds and inactivates endotoxin.The phosphatidylcholine‐phospholipase C (PC‐PLC) inhibitor (D‐609) and the phosphatidate phosphohydrolase inhibitor (propranolol) reduced the LTA‐induced increases in COX‐2 expression and COX activity, while phosphatidylinositol‐phospholipase C inhibitor (U‐73122) had no effect. The PKC inhibitors (Go 6976, Ro 31‐8220 and GF 109203X) and NF‐κB inhibitor, pyrrolidine dithiocarbamate (PDTC), also attenuated the LTA‐induced increases in COX‐2 expression and COX activity.Treatment of A549 cells with LTA caused an increase in PKC activity in the plasma membrane; this stimulatory effect was inhibited by D‐609, propranolol, or Go 6976, but not by U‐73122.Exposure of A549 cells to LTA caused a translocation of p65 NF‐κB from the cytosol to the nucleus and a degradation of IκB‐α in the cytosol. Treatment of A549 cells with LTA caused NF‐κB activation by detecting the formation of NF‐κB‐specific DNA‐protein complex in the nucleus; this effect was inhibited by dexamethasone, D‐609, propranolol, Go 6976, Ro 31‐8220, or PDTC.These results suggest that LTA might activate PC‐PLC and phosphatidylcholine‐phospholipase D to induce PKC activation, which in turn initiates NF‐κB activation, and finally induces COX‐2 expression and PGE2release in human pulmonary epithelial cell line.

Alveolar macrophages are a heterogeneous cell population. The heterogeneity of alveolar macrophages recovered by bronchoalveolar lavage (BAL) from 12 patients with active pulmonary tuberculosis (TB) and 10 normal subjects was studied using Percoll density fractionation. The numbers and subsets (on the basis of CD3, CD4, and CD8 monoclonal antibodies) of lymphocytes in BAL were measured by flow cytometry. Alveolar macrophages recovered from patients with TB were mainly in the lower-density fractions (<1.030 and 1.030 to 1.040 g/ml), whereas alveolar macrophages from normal subjects were in the higher-density fractions (1.050 to 1.070 and >1.070 g/ml). There were no significant differences in alveolar macrophages' repartition between smokers and nonsmokers in either patients with TB or normal subjects. The significant changes in the proportions of the lowest fraction and the higher fractions of alveolar macrophages in patients with TB were not altered after division of our patients into smoker and nonsmoker subgroups when compared with corresponding subgroups in normal subjects. The proportion of the alveolar macrophages in the lowest fraction was inversely related to the bacterial load of sputum and the disease extent on chest radiography in TB patients. The CD4/CD8 ratio was significantly higher in patients with TB. This study shows that alveolar macrophages from TB patients are heterogeneous with hypodense cells predominant probably by interaction with T lymphocytes. Changes in the proportions of alveolar macrophages within subpopulations may be of critical importance in determining the overall response of the lung to TB infection.

We examined the effects of a novel platelet-activating factor (PAF) receptor antagonist, CIS-19 [cis-2-(3,4-dimethoxyphenyl)-6-isopropoxy-7-methoxyl-1-(N-methylformamido)-1,2,3,4-tetrahydronaphthalene], on PAF-induced inflammatory cells recruitment into airways and enhancement of superoxide anion (O - 2) generation from cells retrieved by bronchoalveolar lavage (BAL) in urethane-anesthetized guinea-pigs. Administration of PAF (30 ng/kg, i.v.) produced a selective increase of eosinophils into airways, but no significant increase of the number of macrophages, neutrophils or lymphocytes. CIS-19 (2.5 and 5 mg/kg, i.v.) significantly inhibited the eosinophil recruitment induced by PAF. In vitro, PAF, phorbol 12-myristate 13-acetate (PMA) and N-formyl-methionyl-leucyl-phenylalanine (FMLP) directly stimulated generation of O - 2 from BAL cells in a concentration-dependent manner. CIS-19 (10 -7-10 -4 M) inhibited production of O - 2 induced by PAF (10 -7 M) in a concentration-dependent manner with an EC 50 value of 0.84 µM, but not induced by PMA (0.5 µg/ml) or FMLP (10 -7 M). Administration of PAF (5 ng/kg, i.v.) enhanced markedly PMA (0.5 µg/ml) and FMLP (10 -7 M)-induced generation of O - 2 by 80.2% and 51.3%, respectively. The enhancing effect of PAF was maximal in cells harvested 5 min after the addition ofPAF and then declined to baseline level at 60 min. These responses were inhibited by administration of CIS-19 (0.5–2.5 mg/kg, i.v.) or BN 52021 (5 mg/kg, i.v.). The results indicate that CIS-19 is potent in inhibition of PAF-induced airway inflammatory response and may have therapeutic potential as an anti-inflammatory drugs.

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