Aspirin use is safe in patients undergoing transbronchial lung cryobiopsy.

Background: Aspirin has been shown to be safe for patients undergoing certain diagnostic bronchoscopy procedures, such as transbronchial biopsies and endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration. However, there are no studies documenting the safety of aspirin in patients undergoing trans-bronchial lung cryobiopsy (TBLC). Objective: To determine whether aspirin increases the risk of bleeding during or following TBLC. Methods: 172 consecutive patients undergoing TBLC were included in this retrospective cohort study. Data on demographic characteristics, comorbidities etc. were collected. Bleeding severity was defined by the intervention needed to stop the bleeding: mild-cold saline injection, moderate-adrenalin/hexakarpon injection, or severe - Intensive Care Unit admission after bronchoscopy. Results: Fifty-one patients (29.6 %) were under aspirin treatment at the time of TBLC. Overall, there was no significant difference between the aspirin and the control groups regarding the incidence of moderate-severe bleeding (41.2 % vs. 33.1 %, respectively, p.0.31). the Clopidogrel was found as a risk factor for increased bleeding when taken together with aspirin (Odds ratio = 9.8 (1.1-86), p = 0.013). When taken alone, clopidogrel was also found as a risk factor to increased bleeding, yet these results didn't reach significance due to low number of patients (fig. 1, N = 5, Odds ratio = 2.8 (0.46-17.35), p = 0.245). No difference was observed between the groups regarding additional post-procedural complications, including pneumothorax, hospitalizations, and mortality. Conclusion: To the best of our knowledge, this is the first study examining bleeding risk of cryobiopsy under aspirin treatment. Based on our results, it seems safe to perform TBLC under aspirin treatment, except for patients who are concurrently treated with clopidogrel. Further research should be conducted to substantiate this conclusion.

Transbronchial Cryobiopsy Is Superior to Forceps Biopsy for Diagnosing both Fibrotic and Non-Fibrotic Interstitial Lung Diseases.

BACKGROUND: Interstitial lung disease (ILD) evaluation often requires lung biopsy for definite diagnosis. In recent years, transbronchial cryobiopsy (TBCB) emerged as a procedure with higher diagnostic yield than transbronchial forceps biopsy (TBFB), especially for fibrotic ILDs. Nonetheless, studies comparing these modalities in non-fibrotic ILDs and for specific ILD diagnoses are scarce. OBJECTIVES: The aim of this study was to evaluate the diagnostic yield and safety of TBCB and TBFB in patients with fibrotic and non-fibrotic ILDs. METHOD: An observational retrospective multicenter study including patients with ILD diagnosis by multidisciplinary discussion that underwent TBCB or TBFB between 2017 and 2021. Chest CT scans were reviewed by a chest radiologist. Biopsy specimens were categorized as diagnostic (with specific histological pattern), nondiagnostic, or without lung parenchyma. Nondiagnostic samples were reassessed by a second lung pathologist. TBCB and TBFB diagnostic yields were analyzed by multivariate regression. Procedural complications were evaluated as well. RESULTS: 276 patients were included, 116 (42%) underwent TBCB and 160 (58%) TBFB. Fibrotic ILDs were present in 148 patients (54%). TBCB diagnostic yield was 78% and TBFB 48% (adjusted odds ratio [AOR] 4.2, 95% CI: 2.4-7.6, p < 0.01). The diagnostic yield of TBCB was higher than TBFB among patients with fibrotic ILD (AOR 3.8, p < 0.01), non-fibrotic ILD (AOR 5.8, p < 0.01), and across most ILD diagnoses. TBCB was associated with higher risk for significant bleeding (10% vs. 3%, p < 0.01), but similar risk for pneumothorax. CONCLUSIONS: Diagnostic yield of TBCB was superior to that of TBFB for both fibrotic and non-fibrotic ILDs, and across most diagnoses.

Prostaglandin E2 (PGE2) and Roflumilast Involvement in IPF Progression.

The ECM propagates processes in idiopathic pulmonary fibrosis (IPF), leading to progressive lung scarring. We established an IPF-conditioned matrix (IPF-CM) system as a platform for testing drug candidates. Here, we tested the involvement of a PGE2 and PDE4 inhibitor, Roflumilast, in the IPF-CM system. Primary normal/IPF tissue-derived human lung fibroblasts (N/IPF-HLFs) were cultured on Matrigel and then removed to create the IPF-CM. N-HLFs were exposed to the IPF-CM/N-CM with/without PGE2 (1 nM) and Roflumilast (1 µM) for 24 h. The effect of the IPF-CM on cell phenotype and pro-fibrotic gene expression was tested. In addition, electronic records of 107 patients with up to 15-year follow-up were retrospectively reviewed. Patients were defined as slow/rapid progressors using forced vital capacity (FVC) annual decline. Medication exposure was examined. N-HLFs cultured on IPF-CM were arranged in large aggregates as a result of increased proliferation, migration and differentiation. A PGE2 and Roflumilast combination blocked the large aggregate formation induced by the IPF-CM (p < 0.001) as well as cell migration, proliferation, and pro-fibrotic gene expression. A review of patient records showed that significantly more slow-progressing patients were exposed to NSAIDs (p = 0.003). PGE2/PDE4 signaling may be involved in IPF progression. These findings should be further studied.

Real-Life Diagnostic Performance of the Hypersensitivity Pneumonitis Guidelines: A Multicenter Cohort Study.

Hypersensitivity pneumonitis (HP) is a heterogeneous interstitial lung disease (ILD) that may be difficult to confidently diagnose. Recently, the 2020 ATS/JRS/ALAT HP diagnostic guidelines were published, yet data validating their performance in real-life settings are scarce. We aimed to assess the diagnostic performance of the HP guidelines compared to the gold-standard multidisciplinary discussion (MDD). For this purpose, we included consecutive ILD patients that underwent diagnostic bronchoscopy between 2017 and 2020 in three large medical centers. Four diagnostic factors (antigen exposure history, chest computed tomography pattern, bronchoalveolar lavage lymphocyte count, and histology results) were used to assign guidelines-based HP diagnostic confidence levels for each patient. A sensitivity analysis was performed, with MDD diagnosis as the reference standard. Overall, 213 ILD patients were included, 45 (21%) with an MDD diagnosis of HP. The guidelines' moderate (≥70%) confidence threshold produced optimal performance with 73% sensitivity for HP, 89% specificity, and a J-index of 0.62. The area under the receiver operating characteristic curve (AUC) for a correct guidelines-based diagnosis was 0.86. The guidelines had better performance for non-fibrotic than fibrotic HP (AUC 0.92 vs. 0.82). All diagnostic factors, except bronchoalveolar lavage lymphocyte count, were independent predictors for MDD diagnosis of HP in a multivariate analysis. In conclusion, the HP guidelines exhibited a good diagnostic performance compared to MDD diagnosis in real-life setting.

Chylothorax associated with sarcoidosis: a review of the literature.

OBJECTIVE: To review the medical literature regarding chylothorax associated with sarcoidosis. METHODS: A literature review of all reported cases of sarcoidosis-associated chylothorax, we included a novel case report to the analysis. RESULTS: Of sixteen cases included in the study, 10 were women (62.5%), mean age 47±17years. In 6 subjects (37.5%) chylothorax was part of the initial presentation of sarcoidosis. Four subjects (25%) additionally suffered from lymphedema and chylous ascites, and one from chylous ascites only. Thoracic lymphadenopathy was reported for 13/16 subjects (81.3%) and lung parenchymal disease in 8/16 (50%). Compression of the thoracic duct was considered as a causative factor in 10 cases (62.5%). One case was attributed to granulomatous pleural inflammation, one to generalized lymphangiectasia, and no specific causative factors were identified in 4 remaining cases (25%). Overall mortality rate was 18.8% (3/16 subjects). Of note, all the subjects treated with corticosteroids survived. CONCLUSIONS: Since the association of sarcoidosis with chylothorax is exceedingly rare, alternative etiologies should be pursued even when chylothorax develops in a subject with preexisting sarcoidosis. However, the possibility of sarcoidosis should be entertained when other etiologies for a newly diagnosed chylothorax are ruled out. A multidisciplinary approach is required for optimal management, both for elucidating the diagnosis and for employing therapy, which could be multimodal. A trial of immunosuppressive therapy with corticosteroids should be considered.

The Diagnostic Yield of Endobronchial Ultrasound Transbronchial Needle Aspiration (EBUS-TBNA) in Respiratory Compromised Patients under General Anesthesia.

BACKGROUND: Endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) is a frequently used method for obtaining tissue samples for the diagnosis of various respiratory conditions, including lung cancer staging. In most cases, EBUS-TBNA is performed under moderate sedation (MS). However, in cases of respiratory compromised patients, if this procedure is performed, it is conducted under general anesthesia (GA). OBJECTIVES: To assess the diagnostic yield of EBUS-TBNA among respiratory compromised patients. METHODS: Data of consecutive patients (n=191) who underwent EBUS-TBNA at our medical center between January 2019 and December 2019 were retrospectively analyzed. Respiratory compromised patients underwent GA and patients without respiratory compromise were mostly moderately sedated (MS). Characteristics, diagnostic yield, and complication rates were compared. RESULTS: Diagnostic yield was similar between the two sedation modes (89% in GA group and 78% in the MS group, P = 0.11). The number of total samples obtained per procedure was significantly higher in the GA vs. the MS group (4.1 ± 2.1 vs. 2.1 ± 1.33, P < 0.01). The overall complication rate was 13% and 20.9% in the GA vs. the MS groups, respectively (P = 0.14), with the most frequent complication being minor bleeding. Interestingly, while the number of brushings, bronchoalveolar lavage, and endobronchial biopsy were similar, the percent of subjects who underwent transbronchial biopsy was significantly higher in the GA group (49% vs. 24.2%, P < 0.01). CONCLUSIONS: EBUS-TBNA performed under GA among respiratory compromised patients is safe and has similar diagnostic yield to that of patients without a respiratory compromise.

Hypoxia Inducible Factor 1A Supports a Pro-Fibrotic Phenotype Loop in Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The IPF-conditioned matrix (IPF-CM) system enables the study of matrix-fibroblast interplay. While effective at slowing fibrosis, nintedanib has limitations and the mechanism is not fully elucidated. In the current work, we explored the underlying signaling pathways and characterized nintedanib involvement in the IPF-CM fibrotic process. Results were validated using IPF patient samples and bleomycin-treated animals with/without oral and inhaled nintedanib. IPF-derived primary human lung fibroblasts (HLFs) were cultured on Matrigel and then cleared using NH4OH, creating the IPF-CM. Normal HLF-CM served as control. RNA-sequencing, PCR and western-blots were performed. HIF1α targets were evaluated by immunohistochemistry in bleomycin-treated rats with/without nintedanib and in patient samples with IPF. HLFs cultured on IPF-CM showed over-expression of 'HIF1α signaling pathway' (KEGG, p < 0.0001), with emphasis on SERPINE1 (PAI-1), VEGFA and TIMP1. IPF patient samples showed high HIF1α staining, especially in established fibrous tissue. PAI-1 was overexpressed, mainly in alveolar macrophages. Nintedanib completely reduced HIF1α upregulation in the IPF-CM and rat-bleomycin models. IPF-HLFs alter the extracellular matrix, thus creating a matrix that further propagates an IPF-like phenotype in normal HLFs. This pro-fibrotic loop includes the HIF1α pathway, which can be blocked by nintedanib.

The Short- and Long-Term Impact of Pulmonary Rehabilitation in Subjects with Sarcoidosis: A Prospective Study and Review of the Literature.

BACKGROUND: Sarcoidosis is a heterogeneous multisystemic disorder of unknown etiology. Dyspnea and fatigue are two of the most common and debilitating symptoms experienced by subjects with sarcoidosis. There is limited evidence regarding the short- and long-term impact of pulmonary rehabilitation (PR) on exercise capacity and fatigue in these individuals. OBJECTIVE: To evaluate the benefit of PR in subjects with pulmonary sarcoidosis at different severity stages and to review the current literature about PR in sarcoidosis. METHODS: PR included a 12-week training program of a twice-weekly 90-min workouts. Fifty-two subjects with stable pulmonary sarcoidosis were recruited. Maximal exercise capacity, defined as VO2max, was measured using the cardiopulmonary exercise test (CPET). Pulmonary function tests, 6-min walking distance (6MWD), St. George's Respiratory Questionnaire (SGRQ), and the modified Medical Research Council (mMRC) and Hospital Anxiety and Depression Scale (HADS) questionnaires were given before and after PR and following 6 months (follow-up). RESULTS: The PR program significantly increased the VO2max (1.8 ± 2.3 mL/kg/min, p = 0.002), following 12 weeks. mMRC and SGRQ scores were also improved (-0.3 ± 0.8, p = 0.03, and -3.87 ± 10.4, p = 0.03, respectively). The impact of PR on VO2max was more pronounced in subjects with pulmonary parenchymal involvement. The increase in VO2max correlated with initial disease severity (indicated by FEV1/FVC, p = 0.01). Subjects with FEV1/FVC <70% showed greater improvement in 6MWD. 6MWD also improved in those with a transfer coefficient of the lung for CO (KCO) above 80% predicted (p < 0.05). At 6-month follow-up, the VO2max, 6MWD, and SGRQ scores remained stable, thus suggesting lasting effects of PR. CONCLUSION: PR is a promising complementary therapeutic intervention for subjects with sarcoidosis. Further study is needed to validate these findings.

MiR-608 overexpression in idiopathic pulmonary fibrosis (IPF).

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease that causes scarring of the lungs. The disease is associated with the usual interstitial pneumonia pattern, which was not yet fully recapitulated by an animal model. Therefore, the disease is considered 'human specific'. miRNA-608 is a primate specific miRNA with many potential targets, such CdC42 and Interlukin-6 (IL-6) that were previously implicated in IPF pathology. OBJECTIVE: To test miR-608 expression and its targets in IPF patient samples. METHODS: RNA was extracted from Formalin fixed paraffin embedded tissue sections (N = 18). miRNA-608 and Cdc42 and IL-6 levels were analyzed by qPCR. Acetylcholinesterase (AChE) is another target of miRNA-608. Its' rs17228616 allele has a single-nucleotide polymorphism causing weakened miR-608 interaction (C2098A). Thus, DNA was extracted from whole blood samples from 56 subjects with fibrosing interstitial lung disease and this region was sequenced for assessment of rs17228616 allele polymorphism. RESULTS: miR-608 is significantly overexpressed in IPF samples in comparison with controls (p < 0.05). Cdc42 and IL-6 levels were lower in the IPF patient samples compared with control samples (p < 0.001 and p < 0.05, respectively). The frequency of the rs17228616 minor A-allele was 17/56 (30.4%) with all patients being heterozygous. This result is significant vs. the published Israeli cohort of healthy individuals, which reported 17% prevalence of this allele in healthy control volunteers (p = 0.01, OR = 2.1, CI 95% [1.19-3.9]). CONCLUSION: miR-608 is overexpressed in IPF patients. While the exact mechanism remains to be discovered, it could potentially promote fibrotic disease.

"Severe-controlled" asthma 4 years later: is it still controlled?

BACKGROUND: Controlled severe asthma is based on needing regular medication and 4 markers of good asthma control. This study reevaluated a community sample defined 4 years earlier as "severe-controlled" based on electronic medical records of medications dispensed over 12 months. OBJECTIVES: Determine the current extent of clinically-controlled asthma and asthma-related quality-of-life among patients previously considered "severe-controlled". METHODS: 69 patients considered "severe-controlled" 4 years earlier answered a questionnaire that included the asthma control test (ACT), demographics, education, comorbidities, medications, asthma-related healthcare utilization, atopy history, environmental exposures, and follow-up. Patients underwent spirometry, eosinophil count, total IgE, and skin-prick testing for airborne allergens. RESULTS: Ninety-seven percent reported using combined inhalers (ICS + LABA) regularly. Only 4% visited the ER and none was hospitalized in the last year. Average predicted FEV1 was 80%. Average ACT score was 19; 51% reported recurrent heartburn, 46% night awakenings and 70% recurrent rhinitis. Skin-prick testing was positive in 72%, average IgE was 376 IU/ml. Eosinophil counts were ≥300/ml in 42% and ≥400/ml in 25%. ACT < 20 was strongly related to recurrent heartburn. Formal education was related to ACT ≥ 20 (p = 0.045) and perception of good asthma control the previous month (p < 0.001). Eosinophil count, recurrent heartburn, total IgE, and recurrent rhinitis were interrelated. CONCLUSIONS: Among severe asthmatics, good drug compliance, low use of relievers and low rates of exacerbations do not necessarily reflect asthma-related quality-of-life and optimal control. We urge physicians and HMOs to address asthma control in terms of quality-of-life based on validated questionnaires, and offer all patients asthma education; perhaps more to those with low formal education.

Validation of Lung EpiCheck, a novel methylation-based blood assay, for the detection of lung cancer in European and Chinese high-risk individuals.

AIM: Lung cancer screening reduces mortality. We aim to validate the performance of Lung EpiCheck, a six-marker panel methylation-based plasma test, in the detection of lung cancer in European and Chinese samples. METHODS: A case-control European training set (n=102 lung cancer cases, n=265 controls) was used to define the panel and algorithm. Two cut-offs were selected, low cut-off (LCO) for high sensitivity and high cut-off (HCO) for high specificity. The performance was validated in case-control European and Chinese validation sets (cases/controls 179/137 and 30/15, respectively). RESULTS: The European and Chinese validation sets achieved AUCs of 0.882 and 0.899, respectively. The sensitivities/specificities with LCO were 87.2%/64.2% and 76.7%/93.3%, and with HCO they were 74.3%/90.5% and 56.7%/100.0%, respectively. Stage I nonsmall cell lung cancer (NSCLC) sensitivity in European and Chinese samples with LCO was 78.4% and 70.0% and with HCO was 62.2% and 30.0%, respectively. Small cell lung cancer (SCLC) was represented only in the European set and sensitivities with LCO and HCO were 100.0% and 93.3%, respectively. In multivariable analyses of the European validation set, the assay's ability to predict lung cancer was independent of established risk factors (age, smoking, COPD), and overall AUC was 0.942. CONCLUSIONS: Lung EpiCheck demonstrated strong performance in lung cancer prediction in case-control European and Chinese samples, detecting high proportions of early-stage NSCLC and SCLC and significantly improving predictive accuracy when added to established risk factors. Prospective studies are required to confirm these findings. Utilising such a simple and inexpensive blood test has the potential to improve compliance and broaden access to screening for at-risk populations.

Clinical and Radiological Characteristics of Patients Diagnosed with Spontaneous Pneumothorax: Treatment Options and Clinical Outcomes. A Retrospective Analysis 2004 to 2017.

BACKGROUND: Primary spontaneous pneumothorax (PSP) tends to occur in young adults without underlying lung diseases and is usually followed by limited symptoms, while secondary spontaneous pneumothorax (SSP) is a complication of a pre-existing lung disease. Surprisingly, for such common conditions, there is a considerable inconsistency regarding management guidelines. OBJECTIVES: To evaluate the risk factors for spontaneous pneumothoraxes and to summarize outcomes and complications based on our clinical experience. METHODS: This retrospective study group was comprised of 250 consecutive patients older than 18 years of age who were diagnosed with spontaneous pneumothorax and hospitalized at the Meir Medical Center (2004-2017). Data on demographic characteristics, indicating symptoms, chest X-rays, and chest computed tomography (CT) results were collected. Our experience and outcomes were then compared to a large multicenter study. RESULTS: Most of the patients were male (85%) and past or current smokers; 69% presented with PSP, while the rest were SSP. No occupational relation was noted. About 55% of the cases presented with a moderate or large pneumothorax (over 1/3 hemithorax). Most patients (56%) required chest tube drainage and 20% undergone surgery. Nearly 10% presented with a recurrent pneumothorax with the mean time to recurrence being 11 ± 20 days. Although the length of hospital stay of patients that underwent surgery was the longest (P < 0.001) for both PSP and SSP, the recurrence rate was actually reduced, suggesting some benefit for the surgical treatment option. CONCLUSIONS: Our experience showed that the traditional approach to the PSP treatment should be further considered, as previously suggested.

The Profile of COPD Patients with Prolonged Hospitalizations: A Retrospective Analysis of 200 Hospital Admissions.

BACKGROUND: Patients with severe chronic obstructive pulmonary disease (COPD) experience frequent exacerbations and need to be hospitalized, resulting in an economic and social burden. Although data exist regarding reasons of frequent hospitalizations, there is no data available about the impact on the length of stay (LOS). OBJECTIVES: To characterize the causes of prolonged hospitalizations in COPD patients. METHODS: A retrospective study was conducted of patients who were diagnosed and treated in the pulmonary department for severe COPD exacerbations. All patient demographic data and medical history were collected. Data regarding the disease severity were also collected (including Global Initiative for Obstructive Lung Disease [GOLD] criteria, pulmonologist follow-up, prior hospitalizations, and LOS). RESULTS: The study comprised 200 patients, average age 69.5 ± 10.8 years, 61% males. Of these patients, 89 (45%) were hospitalized for up to 4 days, 111 (55%) for 5 days or more, and 34 (17%) for more than 7 days. Single patients had longer LOS compared with married patients (48% vs. 34%, P = 0.044). Multivariate analysis showed that the number of prior hospital admissions in the last year was a predictor of LOS (P = 0.038, odds ratio [OR] = 0.807, 95% confidence interval [95%CI] = 0.659-0.988), as well as the use of non-invasive respiratory support by bilevel positive airway pressure (BiPAP) during the hospitalization (P = 0.024, OR = 4.662, 95%CI = 1.229-17.681). CONCLUSIONS: Fewer previous hospitalizations due to COPD exacerbations and the need for non-invasive respiratory support by BiPAP were found as predictors of longer LOS.

Inhalation: A means to explore and optimize nintedanib's pharmacokinetic/pharmacodynamic relationship.

Oral nintedanib is marketed for the treatment of idiopathic pulmonary fibrosis (IPF). While effective slowing fibrosis progression, as an oral medicine nintedanib is limited. To reduce side effects and maximize efficacy, nintedanib was reformulated as a solution for nebulization and inhaled administration. To predict effectiveness treating IPF, the nintedanib pharmacokinetic/pharmacodynamic relationship was dissected. Pharmacokinetic analysis indicated oral-delivered nintedanib plasma exposure and lung tissue partitioning were not dose-proportional and resulting lung levels were substantially higher than blood. Although initial-oral absorbed nintedanib efficiently partitioned into the lung, only a quickly eliminated fraction appeared available to epithelial lining fluid (ELF). Because IPF disease appears to initiate and progress near the epithelial surface, this observation suggests short duration nintedanib exposure (oral portion efficiently partitioned to ELF) is sufficient for IPF efficacy. To test this hypothesis, exposure duration required for nintedanib activity was explored. In vitro, IPF-cellular matrix (IPF-CM) increased primary normal human fibroblast (nHLF) aggregate size and reduced nHLF cell count. IPF-CM also increased nHLF ACTA2 and COL1A expression. Whether short duration (inhalation pharmacokinetic mimic) or continuous exposure (oral pharmacokinetic mimic), nintedanib (1-100 nM) reversed these effects. In vivo, intubated silica produced a strong pulmonary fibrotic response. Once-daily (QD) 0.021, 0.21 and 2.1 mg/kg intranasal (IN; short duration inhaled exposure) and twice-daily (BID) 30 mg/kg oral (PO; long duration oral exposure) showed that at equivalent-delivered lung exposure, QD short duration inhaled nintedanib (0.21 mg/kg IN vs. 30 mg/kg PO) exhibited equivalent-to-superior activity as BID oral (reduced silica-induced elastance, alpha-smooth muscle actin, interleukin-1 beta (IL-1ß) and soluble collagen). Comparatively, the increased inhaled lung dose (2.1 mg/kg IN vs. 30 mg/kg PO) exhibited increased effect by further reducing silica-induced elastance, IL-1ß and soluble collagen. Neither oral nor inhaled nintedanib reduced silica-induced parenchymal collagen. Both QD inhaled and BID oral nintedanib reduced silica-induced bronchoalveolar lavage fluid macrophage and neutrophil counts with oral achieving significance. In summary, pharmacokinetic elements important for nintedanib activity can be delivered using infrequent, small inhaled doses to achieve oral equivalent-to-superior pulmonary activity.

Integrin alpha-5 silencing leads to myofibroblastic differentiation in IPF-derived human lung fibroblasts.

BACKGROUND AND OBJECTIVE: The term 'fibroblast' covers a heterogeneous cell population in idiopathic pulmonary fibrosis (IPF). The fibroblasts are considered as main effector cells, because they promote disease progression by releasing exaggerated amounts of extracellular matrix proteins and modifying cell microenvironment. As IPF-derived human lung fibroblasts (IPF-HLFs) were shown to express higher levels of integrin alpha-5 (ITGA5) than normal derived HLFs (N-HLFs), we explored the importance of ITGA5 to IPF progression. METHODS: IPF-HLF and N-HLF primary cultures were established. ITGA5 was silenced by specific small interfering RNA (siRNA)s and its effects on cell phenotype (e.g. cell number, size, cell death, migration) and gene expression (e.g. RNA sequencing, quantitative polymerase chain reaction [qPCR], western blot and immunofluorescence) were tested. Specific integrin expression was evaluated in IPF patient formalin-fixed paraffin embedded sections by immunohistochemistry (IHC). RESULTS: ITGA5-silencing resulted in reduced IPF-HLF proliferation rates and cell migration (p < 0.05), as well as elevated cell death. transforming growth factor beta (TGF-ß) targets (e.g. Fibronectin (FN1), Matrix metalloproteinase 2 (MMP2), TGFB1) were surprisingly elevated following ITGA5 silencing (p < 0.05). N-HLFs, however, were only slightly affected. Interestingly, ITGA5-silenced cells differentiated into myofibroblasts (e.g. elevated alpha-smooth muscle actin [αSMA], collagen1a, large cell size). RNA-sequencing revealed that following differentiation on 3D-Matrigel for 24 h, ITGA5 levels are reduced while integrin alpha-8 (ITGA8) are elevated in IPF-HLFs. This was confirmed in IPF patients, in which ITGA5 was mainly found in fibroblastic foci, while ITGA8 was mostly observed in old fibrous tissue in the same patient. CONCLUSIONS: ITGA5 expression facilitates a more aggressive proliferative phenotype. Downregulation of this integrin results in myofibroblastic differentiation, which is accompanied by elevated ITGA8. Specific targeting could present a therapeutic benefit.

Systemic Thrombolysis Therapy is Associated With Improved Outcomes Among Patients With Acute Pulmonary Embolism and Respiratory Failure.

BACKGROUND: Thrombolytic therapy is widely accepted for massive pulmonary embolism (PE) due to the high mortality risk associated with standard anticoagulation alone. Its role in submassive PE, however, has remained controversial. We aimed to evaluate whether the selective use of systemic thrombolytic therapy with intravenous tissue plasminogen activator (IV-tPA) improves the survival of patients with submassive PE at increased risk for clinical deterioration. METHODS: A total of 184 consecutive patients diagnosed with acute PE by chest thoracic angiography (CTA) were included in a retrospective study. Pulmonary artery obstruction and right/left ventricular dysfunction were evaluated by CTA and echocardiography. Medical history and simplified PE Severity Index (sPESI) were assessed at diagnosis. Hemodynamic and respiratory status were recorded at diagnosis, admission to pulmonary unit and prior to thrombolytic therapy. Patient survival was assessed at 30 of 90 days from diagnosis by CTA. RESULTS: All low risk patients (36%) per sPESI survived. Among the 117 remaining patients, 31% received IV-tPA. Respiratory failure was associated with decreased age-adjusted survival (P = 0.005). Among patients with respiratory failure selected for IV-tPA, age-adjusted survival was improved significantly compared to others (P = 0.043). CONCLUSIONS: Thrombolytic therapy for hemodynamically stable PE patients with respiratory failure may improve survival. TRIAL REGISTRATION: MMC-0216-14.