Prevalence and Clinical Implications of Nontuberculous Mycobacteria Isolation and Infection among Patients with Bronchiectasis in the Jerusalem Area.

BACKGROUND: Bronchiectasis is an obstructive chronic lung disease characterized by structural changes in large and small airways, namely permanent widening of bronchial lumen resulting in chronic inflammation and infection. Nontuberculous mycobacteria (NTM) are environmental mycobacteria that may cause human infection or colonization with over 150 species identified to date. Bronchiectasis with NTM colonization or infection is often encountered but with varying prevalence and unknown clinical or prognostic significance. OBJECTIVES: To find the prevalence of NTM among patients with bronchiectasis in the Jerusalem district. To assess whether there were clinical differences between patients with bronchiectasis who were isolated with NTM and those without. METHODS: In this retrospective observational research study, we reviewed all computerized medical charts of patients over 18 years of age, who were diagnosed with bronchiectasis at Hadassah Medical Centers in Jerusalem between 2012 and 2017. We assessed the prevalence of NTM pulmonary disease. To compare patients with and without NTM, we reviewed and analyzed clinical, radiological, and microbiological data of all NTM patients and a group of controls in a 4:1 ratio. RESULTS: Prevalence of NTM among bronchiectasis patients was 5.1%, slightly lower than previously reported in Israel. We did not find clinically or radiological significant differences in patients with NTM disease compared to controls. This result included a similar number of exacerbations, hospitalization rates, number of lobes involved, and pulmonary function tests. CONCLUSIONS: Bronchiectasis patients with isolation of Pseudomonas aeruginosa experienced more exacerbations than patients with other isolates, consistent with previous studies.

Single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol versus dual therapy in current and former smokers with COPD: IMPACT trial post hoc analysis.

BACKGROUND: Smoking is the major risk factor for chronic obstructive pulmonary disease (COPD). In IMPACT, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy significantly reduced moderate/severe exacerbation rates and improved lung function and health status versus FF/VI or UMEC/VI in COPD patients. This post hoc analysis investigated trial outcomes by smoking status. METHODS: IMPACT was a double-blind, 52-week trial. Patients aged ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the prior year were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg. Endpoints assessed by smoking status at screening included rate and risk of moderate/severe exacerbations, change from baseline in trough forced expiratory volume in 1 s, and St George's Respiratory Questionnaire total score at Week 52. Safety was also assessed. RESULTS: Of the 10,355 patients in the intent-to-treat population, 3,587 (35%) were current smokers. FF/UMEC/VI significantly reduced on-treatment moderate/severe exacerbation rates versus FF/VI and UMEC/VI in current (rate ratio 0.85 [95% confidence interval: 0.77-0.95]; P = 0.003 and 0.86 [0.76-0.98]; P = 0.021) and former smokers (0.85 [0.78-0.91]; P < 0.001 and 0.70 [0.64-0.77]; P < 0.001). FF/UMEC/VI significantly reduced time-to-first on-treatment moderate/severe exacerbation versus FF/VI and UMEC/VI in former smokers, and versus FF/VI in current smokers. Similar trends were seen for lung function and health status. Former smokers receiving inhaled corticosteroid-containing therapy had higher pneumonia incidence than current smokers. CONCLUSIONS: FF/UMEC/VI improved clinical outcomes versus dual therapy regardless of smoking status. Benefits of FF/UMEC/VI versus UMEC/VI were greatest in former smokers, potentially due to relative corticosteroid resistance in current smokers. CLINICAL TRIAL REGISTRATION: GSK (CTT116855/NCT02164513).

Lung Regeneration by Transplantation of Allogeneic Lung Progenitors Using a Safer Conditioning Regimen and Clinical-grade Reagents.

Over the last decades, several studies demonstrated the possibility of lung regeneration through transplantation of various lung progenitor populations. Recently, we showed in mice that fetal or adult lung progenitors could potentially provide donor cells for transplantation, provided that the lung stem cell niche in the recipient is vacated of endogenous lung progenitors by adequate conditioning. Accordingly, marked lung regeneration could be attained following i.v. infusion of a single cell suspension of lung cells into recipient mice conditioned with naphthalene (NA) and 6Gy total body irradiation (TBI). As clinical translation of this approach requires the use of allogenic donors, we more recently developed a novel transplantation modality based on co-infusion of hematopoietic and lung progenitors from the same donor. Thus, by virtue of hematopoietic chimerism, which leads to immune tolerance toward donor antigens, the lung progenitors can be successfully engrafted without any need for post-transplant immune suppression. In the present study, we demonstrate that it is possible to replace NA in the conditioning regimen with Cyclophosphamide (CY), approved for the treatment of many diseases and that a lower dose of 2 GY TBI can successfully enable engraftment of donor-derived hematopoietic and lung progenitors when CY is administered in 2 doses after the stem cell infusion. Taken together, our results suggest a feasible and relatively safe protocol that could potentially be translated to clinical transplantation of lung progenitors across major MHC barriers in patients with terminal lung diseases.

Predictors of malignant lymph node involvement in patients with mediastinal lymphadenopathy and previous cancer: A cohort study.

BACKGROUND: Mediastinal lymphadenopathy is a common finding in follow-up after diagnosis of malignancy, and may represent recurrence of malignancy, or benign processes such as sarcoidosis. CT and PET-CT are commonly used, despite limited ability to discriminate between benign and malignant disease, and although EBUS-guided bronchoscopy is often performed, it is relatively invasive and may not always be safe in high-risk patients. Clinical and radiological predictors for cancer recurrence could therefore be of value. METHODS: A retrospective cohort analysis of all patients with mediastinal lymphadenopathy and previous malignancy undergoing mediastinal lymph node sampling via bronchoscopy was undertaken. Demographics, smoking status, details of previous malignancy, time since cancer diagnosis, and imaging data were collected, as well as follow-up in the years following the procedure. We then compared specific characteristics of patients with malignant and benign lymphadenopathy in order to identify predictors of malignant versus benign lymphadenopathy. RESULTS: A total of 113 patients were analyzed of which 63% had tumor recurrence, while the rest had benign disease including sarcoidosis. Smoking history and previous lung cancer were both correlated with lymph node malignancy, while symmetric hilar enlargement, and the presence of multiple pathological stations were correlated with benign outcome. Size, maximal SUV uptake or time interval since cancer diagnosis were not associated with the final diagnosis. CONCLUSIONS: These findings may help in assessing the pretest probability of tumor recurrence in patients with mediastinal lymphadenopathy, thus aiding in the clinical decision-making in such scenarios.

Possible association between SP-C mutations and lung cancer: Two case reports and review of literature.

Surfactant protein C (SP-C) is one of four surfactant proteins produced by type II pneumocytes. Mutations in surfactant protein A are strongly associated with development of lung cancer. Mutations in the SP-C gene are rare and are associated with interstitial lung disease in the pediatric age group. We describe two patients with SP-C mutations who developed lung cancer. Both patients had concurrent interstitial lung disease, although the clinical phenotype was variable. In both cases, mutations were in translated region of the SP-C gene; one in the BRICHOS domain and the other in the transmembrane domain. Our paper suggests that patients with SP-C mutations can be at increased risk for the development of lung cancer, and it's reasonable to follow them routinely.

Waterpipe smoking: a review of pulmonary and health effects.

Waterpipe smoking is an old form of tobacco smoking, originating in Persia and the Middle East. The popularity of the waterpipe is increasing worldwide, particularly among young adults, and there are widespread misconceptions regarding its negative health effects. The inhaled smoke of the waterpipe contain several toxic and hazardous materials including nicotine, tar, polyaromatic hydrocarbons and heavy metals, all of which are proven to be related to lung diseases and cancer. Regular waterpipe smoking is associated with respiratory symptoms, a decrease in pulmonary function and increased risk for lung disease such as COPD. Additional negative health effects include increased risk for arterial stiffness, ischaemic heart disease and several cancer types including lung cancer. This review summarises the negative health effects of waterpipe smoking, with emphasis on cardiorespiratory complications. Increased awareness and knowledge amongst healthcare professionals will hopefully help identify waterpipe smokers and promote patient education. Applying World Health Organization (WHO) regulations will provide a synergistic effect in reducing waterpipe use and associated disease.

The Effect of a Multidisciplinary Integrated Approach on Outcomes in Chronic Obstructive Pulmonary Disease.

BACKGROUND: Chronic obstructive pulmonary disease(COPD) is a common and debilitating condition, often accompanied by other co-morbidities. The Hadassah Medical Center'smulti-disciplinary approach in treating COPD patients in a one-stop shopfor COPD patients is the first of its kind in Israel. It includes pulmonary physicians, a nurse coordinator, dietitian, psychotherapist, physiotherapist, and a smoking cessation program. OBJECTIVES: To characterize efficacy of such a program in COPD patients. METHODS: Demographic and clinical data from patients referred to the Hadassah COPD center, including co-morbidities, baseline symptoms (using the CAT questioner), spirometry results, 6-minute walking distance (6MWD) test and current treatment were collected and compared to the same data after 6-12 months of treatment. RESULTS: Some 154 patients were evaluated; mean age 64 years; 67% male; 53% current smokers. Only 74% received chronic treatment for COPD. Average body mass index was 28, CAT score 21.3, and mean FEV1 was 1.38 liters (53% of predicted).The mean exacerbation rate during the year prior to referral was 1.72 with a 1.07 annual admission rate. Following treatment, a small increase was noted in FEV1 to 1.47 liters, 54.4% of predicted; improvement in CAT scores to 16.5 with improvement seen in 70% of patients, and a 42 meter increase in the 6MWD (from 344 to 386 meters) with some improvement of effort capacity in 77% of patients. The rate of smokers decreased to 21%, and 97% of patients received medical treatment for COPD. CONCLUSIONS: Multidisciplinary approach is feasible and efficacious in patients with COPD.

Prophylactic use of tranexamic acid for prevention of bleeding during transbronchial lung biopsies - A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although massive bleeding following transbronchial lung biopsies (TBLB) is rare, even minor hemorrhage may prolong the procedure and result in inadequate sampling. Tranexamic acid (TXA) is an antifibrinolytic agent, which reduces bleeding in numerous scenarios, however, its prophylactic use in mitigating post-TBLB bleeding has not been investigated. We conducted a prospective, randomized, double-blind, placebo-controlled trial to determine whether topical infusion of TXA prior to TBLB would reduce bleeding, shorten procedure duration and increase the number of biopsies obtained. METHODS: We blindly randomized patients undergoing TBLB to receive topical TXA or placebo in the lobar bronchus prior to biopsies. Vital signs, procedure length, fluid balance (as a measure of the amount of bleeding), operator's assessment of bleeding, and number of biopsies obtained were measured. Data was analyzed using the two-tailed Student's T-Test, Chi-square or Mann-Whitney tests as appropriate. RESULTS: Fifty patients were randomized, 26 to the TXA arm. The bleeding in the TXA group was significantly lower (P = 0.0037), with more specimens being obtained (placebo 7 (6, 9) (median and interquartile range) vs. TXA 9 (8, 10), P = 0.023) and no difference in procedure length (placebo 30 min (29.3, 34.3) vs. TXA 30 (24.8, 36), P = 0.90). There were no clinically significant adverse events in any of the groups up to one month of follow up. CONCLUSION: Endobronchial installation of TXA prior to obtaining TBLB results in less bleeding and allows more biopsies to be obtained with no additional adverse events. The prophylactic use of TXA during TBLB may be considered as standard.

Forefront: MiR-34a-Knockout Mice with Wild Type Hematopoietic Cells, Retain Persistent Fibrosis Following Lung Injury.

MicroRNAs (miRs) are known to limit gene expression at the post-transcriptional level and have important roles in the pathogenesis of various conditions, including acute lung injury (ALI) and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). In this study, we found increased levels of miR-34 at times of fibrosis resolution following injury, in myofibroblasts from Bleomycin-treated mouse lungs, which correlates with susceptibility to cell death induced by immune cells. On the contrary, a substantial downregulation of miR-34 was detected at stages of evolution, when fibroblasts resist cell death. Concomitantly, we found an inverse correlation between miR-34 levels with that of the survival molecule FLICE-like inhibitory protein (FLIP) in lung myofibroblasts from humans with IPF and the experimental model. Forced upregulation of miR-34 with miR-34 mimic in human IPF fibrotic-lung myofibroblasts led to decreased cell survival through downregulation of FLIP. Using chimeric miR-34 knock-out (KO)-C57BL/6 mice with miR34KO myofibroblasts but wild-type (WT) hematopoietic cells, we found, in contrast to WT mice, increased and persistent FLIP levels with a more severe fibrosis and with no signs of resolution as detected in pathology and collagen accumulation. Moreover, a mimic of miR-34a decreased FLIP expression and susceptibility to cell death was regained in miR-34KO fibroblasts. Through this study, we show for the first time an inverse correlation between miR-34a and FLIP expression in myofibroblasts, which affects survival, and accumulation in lung fibrosis. Reprogramming fibrotic-lung myofibroblasts to regain susceptibility to cell-death by specifically increasing their miR34a and downregulating FLIP, may be a useful strategy, enabling tissue regeneration following lung injury.

Rapid shortening of leukocyte telomeres is associated with poorer pulmonary function among healthy adults.

AIM: The study aimed to examine the association between leukocyte telomere length (LTL) attrition over 13 years (between mean age 30 and mean age 43) and lung function at mean age 50. MATERIALS & METHODS: In a longitudinal observational study LTL was determined twice on a population-based sample of 481 Jewish residents of Jerusalem at mean ages 30 and 43 years. Pulmonary function was determined at mean age 50 years. Multiple linear regression and multivariable ordinal logistic modeling were applied. Akaike's Information Criteria (AIC) was used for model selection. RESULTS: In unadjusted analysis, Forced Expiratory Volume in 1 s (FEV1%) was inversely associated with the LTL attrition rate (standardized beta = -0.110, P = 0.023) but not with the baseline LTL. Forced Vital Capacity (FVC%) was inversely associated with the LTL attrition rate (standardized beta = -0.108, P = 0.026). Multivariable adjustment mildly attenuated the association with the LTL attrition rate (standardized beta = -0.100, P = 0.034 for FEV1% and -0.093, P = 0.042 for FVC%). This would be consistent with a 3.3% [95% Confidence Interval (CI): 3.1-3.4%] decline in FEV1% and a 3.0% (95% CI:2.8-3.1%) decline in FVC% per year. In linear regression models the LTL-pulmonary function association did not differ by sex, social mobility, pack-years smoking exposure, or level of GlycA, a novel systemic inflammatory marker. CONCLUSIONS: Greater LTL attrition between mean age 30 and mean age 43 was associated with poorer lung function at mean age 50 years. The availability of longitudinal data on LTL attrition for the first time in the current study strengthens the case for LTL change preceding change in lung function.

Lung Injury Repair by Transplantation of Adult Lung Cells Following Preconditioning of Recipient Mice.

Repair of injured lungs represents a longstanding therapeutic challenge. We recently demonstrated that human and mouse embryonic lung tissue from the canalicular stage of development are enriched with lung progenitors, and that a single cell suspension of canalicular lungs can be used for transplantation, provided that lung progenitor niches in the recipient mice are vacated by strategies similar to those used in bone marrow transplantation. Considering the ethical limitations associated with the use of fetal cells, we investigated here whether adult lungs could offer an alternative source of lung progenitors for transplantation. We show that intravenous infusion of a single cell suspension of adult mouse lungs from GFP+ donors, following conditioning of recipient mice with naphthalene and subsequent sublethal irradiation, led to marked colonization of the recipient lungs, at 6-8 weeks post-transplant, with donor derived structures including epithelial, endothelial, and mesenchymal cells. Epithelial cells within these donor-derived colonies expressed markers of functionally distinct lung cell types, and lung function, which is significantly compromised in mice treated with naphthalene and radiation, was found to be corrected following transplantation. Dose response analysis suggests that the frequency of patch forming cells in adult lungs was about threefold lower compared to that found in E16 fetal lungs. However, as adult lungs are much larger, the total number of patch forming cells that can be collected from this source is significantly greater. Our study provides proof of concept for lung regeneration by adult lung cells after preconditioning to vacate the pulmonary niche. Stem Cells Translational Medicine 2018;7:68-77.

The effect of omalizumab treatment on the low affinity immunoglobulin E receptor (CD23/fc epsilon RII) in patients with severe allergic asthma.

BACKGROUND: Omalizumab is an anti-immunoglobulin E (IgE) monoclonal antibody used in the treatment of severe asthma. Its therapeutic efficacy is primarily attributed to reduction of serum-free IgE and in the expression of high-affinity IgE receptor, fc epsilon RI. However, its effect on the low-affinity IgE receptor fc epsilon RII/CD23 in vivo has not been evaluated. AIM: To determine whether CD23 plays a role in the inflammatory process in severe uncontrolled asthma and whether anti-IgE therapy modulates fc epsilon RII/CD23 expression in these patients. METHODS: We evaluated the expression of IgE receptors fc epsilon RI, fc epsilon RII/CD23, and soluble CD23 (sCD23), and the activation state of peripheral blood monocytes (tumor necrosis factor alpha, interleukin (IL) 1-beta, transforming growth factor (TGF) beta expression) in the patients with severe asthma before and after 24 weeks of omalizumab treatment and in the healthy controls. Cytokine expression of monocytes in response to different stimulation (IL-4, IL-4 plus IgE, IL-4 plus IgE plus anti-IgE, and IL-4 plus IgE plus anti-IgE plus anti-CD23 for 72 hours) was determined by enzyme-linked immunosorbent assay. RESULTS: Treatment with omalizumab (for 24 weeks) improved disease control and pulmonary function (forced expiratory volume in the first second of expiration, 64.5 versus 74%; p = 0.021). Mean ± SE expression of fc epsilon RI on monocytes was higher in the patients with asthma versus the controls (45.7 ± 12.2% versus 18.6 ± 5.8%; p = 0.04) and was reduced after omalizumab treatment (45.7 ± 12.2% versus 15.6 ± 4.4%; p = 0.027). Mean ± SE TGF-beta levels in supernatants from monocytes were reduced in the patients treated with omalizumab (211 ± 6 pg/mL versus 184 ± 9 pg/mL; p = 0.036). CONCLUSION: Modulation of the low affinity IgE receptor CD23 in severe asthma is complex, and sCD23 may inversely reflect disease activity. Treatment with omalizumab was associated with reduced monocyte activation.

The association between osteopontin gene polymorphisms, osteopontin expression and sarcoidosis.

BACKGROUND: Sarcoidosis is a systemic inflammatory disease of unknown etiology. Osteopontin (SPP1, OPN) is an extra cellular matrix glycoprotein and cytokine with a known role in granuloma formation and in autoimmune and inflammatory diseases. OBJECTIVE: To determine whether plasma OPN levels are elevated in patients with sarcoidosis and compare the frequency of four single nucleotide polymorphism (SNPs) variants in the OPN gene in sarcoidosis patients compared to healthy controls. METHODS: Demographic and clinical information, radiological studies and pulmonary function tests were evaluated in 113 patients with sarcoidosis and in 79 healthy controls. Blood samples were analyzed for SNPs of the OPN gene and for plasma OPN and CRP levels. Association between clinical features of disease and OPN levels as well as SNP frequencies was determined. RESULTS: Plasma OPN levels were higher in sarcoidosis patients than in healthy subjects, (median: 217 vs 122ng/ml, p<0.001). Area under the curve for receiver operator curves (ROC) was 0.798 (0.686-0.909 95% CI.) No differences were observed between sarcoidosis patients and controls in the frequency of any of the SNPs evaluated. Presence of lung parenchymal involvement was associated with SNP distribution at rs1126772 (p = 0.02). We found no correlation between SNPs distribution and plasma OPN levels. CONCLUSIONS: Osteopontin protein levels are elevated in sarcoidosis. We found no evidence for an association between SNPs on the osteopontin gene and plasma OPN levels or the presence of sarcoidosis, however, an association between genotype and several phenotypic clinical parameters of disease was observed.

Characteristics of Sarcoidosis in Patients with Previous Malignancy: Causality or Coincidence?

BACKGROUND: The association between sarcoidosis and malignancy is poorly defined. Sarcoidosis can precede, be diagnosed concurrently with, or follow malignancy. OBJECTIVES: We describe the clinical and radiological features of patients with sarcoidosis following malignancy to determine whether this association is causal or coincidental. METHODS: We performed a search for all patients with confirmed sarcoidosis following malignancy in our institution during 2001-2015. Clinical and radiological features, bronchoscopic findings, bronchoalveolar lavage cell counts, and pulmonary function tests (PFTs) were reviewed to evaluate patterns of disease involvement. Details of the histological type of cancer, staging, treatment, and follow-up were reviewed. RESULTS: Twenty-nine patients were identified. The most prevalent malignancies were breast cancer and lymphoma (24% each). Based on the incidence of these malignancies, we estimated the incidence of sarcoidosis was 175 times higher after lymphoma and 38 times higher after breast cancer as compared to the general population. Most patients had early stage cancer (stage I, II) (75%), and only 2 patients (7%) had recurrence of their malignancy after diagnosis of sarcoidosis. Sarcoidosis was diagnosed within 5 years of malignancy in over half the patients, 76% were asymptomatic and 69% had normal PFTs. Mediastinal lymphadenopathy was present in 81% of cases, hilar lymphadenopathy in 67%, and pulmonary parenchymal involvement in 41%. Fifty percent of patients had received Adriamycin, 38% cyclophosphamide, and 33% vincristine. CONCLUSIONS: Sarcoidosis following malignancy is indistinguishable from "idiopathic" sarcoidosis, although it is frequently asymptomatic. The high frequency of sarcoidosis after specific cancers but not others, suggests a causative association between malignancy and development of sarcoidosis.

Tocilizumab Promotes Regulatory T-cell Alleviation in STAT3 Gain-of-function-associated Multi-organ Autoimmune Syndrome.

PURPOSE: Signal transducer and activator of transcription 3 is a member of a family of proteins involved in the regulation of inflammation, differentiation, proliferation, and survival of cells. Here we describe a 38-year-old male who has experienced gastrointestinal, dermatologic, pulmonary, and malignant manifestations. METHODS: Whole-exome sequencing, validated by Sanger sequencing, was performed after extensive investigations. FINDINGS: Whole-exome sequencing revealed a heterozygous missense mutation in the signal transducer and activator of transcription 3 gene, c.1261G>A (p.G421R). Fluorescence-activated cell sorting analysis of peripheral T lymphocytes revealed low levels of CD4+CD25+FoxP3 and CD8+CD25+FoxP3 regulatory T cells. After treatment with 2 cycles of tocilizumab, an interleukin-6 receptor antibody, a significant increase in the level of regulatory T cells was observed, accompanied by clinical improvement. IMPLICATIONS: This case sheds light on the emerging role of signal transducer and activator of transcription 3 gain-of-function mutation in the pathogenesis of autoimmune diseases, and further addresses the therapeutic role of interleukin-6 blocker treatment in this syndrome.

Pyruvate dehydrogenase has a major role in mast cell function, and its activity is regulated by mitochondrial microphthalmia transcription factor.

BACKGROUND: We have recently observed that oxidative phosphorylation-mediated ATP production is essential for mast cell function. Pyruvate dehydrogenase (PDH) is the main regulator of the Krebs cycle and is located upstream of the electron transport chain. However, the role of PDH in mast cell function has not been described. Microphthalmia transcription factor (MITF) regulates the development, number, and function of mast cells. Localization of MITF to the mitochondria and its interaction with mitochondrial proteins has not been explored. OBJECTIVE: We sought to explore the role played by PDH in mast cell exocytosis and to determine whether MITF is localized in the mitochondria and involved in regulation of PDH activity. METHODS: Experiments were performed in vitro by using human and mouse mast cells, as well as rat basophil leukemia cells, and in vivo in mice. The effect of PDH inhibition on mast cell function was examined. PDH interaction with MITF was measured before and after immunologic activation. Furthermore, mitochondrial localization of MITF and its effect on PDH activity were determined. RESULTS: PDH is essential for immunologically mediated degranulation of mast cells. After activation, PDH is serine dephosphorylated. In addition, for the first time, we show that MITF is partially located in the mitochondria and interacts with PDH. This interaction is dependent on the phosphorylation state of PDH. Furthermore, mitochondrial MITF regulates PDH activity. CONCLUSION: The association of mitochondrial MITF with PDH emerges as an important regulator of mast cell function. Our findings indicate that PDH could arise as a new target for the manipulation of allergic diseases.

Preconditioning allows engraftment of mouse and human embryonic lung cells, enabling lung repair in mice.

Repair of injured lungs represents a longstanding therapeutic challenge. We show that human and mouse embryonic lung tissue from the canalicular stage of development (20-22 weeks of gestation for humans, and embryonic day 15-16 (E15-E16) for mouse) are enriched with progenitors residing in distinct niches. On the basis of the marked analogy to progenitor niches in bone marrow (BM), we attempted strategies similar to BM transplantation, employing sublethal radiation to vacate lung progenitor niches and to reduce stem cell competition. Intravenous infusion of a single cell suspension of canalicular lung tissue from GFP-marked mice or human fetal donors into naphthalene-injured and irradiated syngeneic or SCID mice, respectively, induced marked long-term lung chimerism. Donor type structures or 'patches' contained epithelial, mesenchymal and endothelial cells. Transplantation of differentially labeled E16 mouse lung cells indicated that these patches were probably of clonal origin from the donor. Recipients of the single cell suspension transplant exhibited marked improvement in lung compliance and tissue damping reflecting the energy dissipation in the lung tissues. Our study provides proof of concept for lung reconstitution by canalicular-stage human lung cells after preconditioning of the pulmonary niche.

Cyclic nitroxide radicals attenuate inflammation and Hyper-responsiveness in a mouse model of allergic asthma.

The effects of stable cyclic nitroxide radicals have been extensively investigated both in vivo and in vitro demonstrating anti-inflammatory, radioprotective, anti-mutagenic, age-retardant, hypotensive, anti-cancer and anti-teratogenic activities. Yet, these stable radicals have not been evaluated in asthma and other airway inflammatory disorders. The present study investigated the effect of 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (TPL) and 3-carbamoyl-proxyl (3-CP) in a mouse model of ovalbumin (OVA)-induced allergic asthma. Both 3-CP and TPL were non-toxic when administered either orally (1% w/w nitroxide-containing chow) or via intraperitoneal (IP) injection (∼300 mg/kg). Feeding the mice orally demonstrated that 3-CP was more effective than TPL in reducing inflammatory cell recruitment into the airway and in suppressing airway hyper-responsiveness (AHR) in OVA-challenged mice. To characterize the optimal time-window of intervention and mode of drug administration, 3-CP was given orally during allergen sensitization, during allergen challenge or during both sensitization and challenge stages, and via IP injection or intranasal instillation for 3 days during the challenge period. 3-CP given via all modes of delivery markedly inhibited OVA-induced airway inflammation, expression of cytokines, AHR and protein nitration of the lung tissue. Oral administration during the entire experiment was the most efficient delivery of 3-CP and was more effective than dexamethasone a potent corticosteroid used for asthma treatment. Under a similar administration regimen (IP injection before the OVA challenge), the effect of 3-CP was similar to that of dexamethasone and even greater on AHR and protein nitration. The protective effect of the nitroxides, which preferentially react with free radicals, in suppressing the increase of main asthmatic inflammatory markers substantiate the key role played by reactive oxygen and nitrogen species in the molecular mechanism of asthma. The present results demonstrate the therapeutic potential of nitroxides for the treatment of asthma.

Pulmonary epithelioid hemangioendothelioma.

Pulmonary epithelioid hemangioendothelioma (PEH), previously known as "intravascular bronchoalveolar tumor," is a rare vascular malignancy with an unpredictable prognosis. Treatment can vary from observation in asymptomatic patients to surgery in patients with resectable disease or chemotherapy in patients with disseminated disease. This report describes the clinical, radiological and pathological features of three cases of PEH and a review of the current literature.