Lung transplantation provides a treatment option for many individuals with advanced lung disease due to cystic fibrosis (CF). Since the first transplants for CF in the 1980s, survival has improved ...and the opportunity for transplant has expanded to include individuals who previously were not considered candidates for transplant. Criteria to be a transplant candidate vary significantly among transplant programs, highlighting that the engagement in more than one transplant program may be necessary. Individuals with highly resistant CF pathogens, malnutrition, osteoporosis, CF liver disease, and other comorbidities may be suitable candidates for lung transplant, or if needed, multi-organ transplant. The transplant process involves several phases, from discussion of prognosis and referral to a transplant center, to transplant evaluation, to listing, transplant surgery, and care after transplant. While the availability of highly effective CF transmembrane conductance regulator (CFTR) modulators for many individuals with CF has improved lung function and slowed progression to respiratory failure, early discussion regarding transplant as a treatment option and referral to a transplant program are critical to maximizing opportunity and optimizing patient and family experience. The decision to be evaluated for transplant and to list for transplant are distinct, and early referral may provide a treatment option that can be urgently executed if needed. Survival after transplant for CF is improving, to a median survival of approximately 10 years, and most transplant survivors enjoy significant improvement in quality of life.
The development of CFTR modulators has been one of the most remarkable stories in respiratory medicine. Defining the genetic, molecular, and cellular biology of cystic fibrosis (CF) mutations enabled ...high-throughput screening to identify compounds that partially restore CFTR function. The first highly effective CFTR modulator became available in 2012 when the US Food and Drug Administration approved ivacaftor for individuals with the G551D CFTR mutation. IVA substantially decreased sweat chloride, increased respiratory function, promoted weight gain, reduced exacerbation frequency, and improved the quality of life for patients with an FEV1 40-90% predicted. Several studies have examined the effect of IVA on patients with advanced lung disease and demonstrated similar improvements to what was observed in patients with modest lung disease. Here, Burgel and colleagues report the effect of ETI for individuals with CF and advanced lung disease who received ETI through an early access program in France.
Type 2 insulin-like growth factor (IGF-II) levels are increased in fibrosing lung diseases such as idiopathic pulmonary fibrosis (IPF) and scleroderma/systemic sclerosis-associated pulmonary fibrosis ...(SSc). Our goal was to investigate the contribution of IGF receptors to IGF-II-mediated fibrosis in these diseases and identify other potential mechanisms key to the fibrotic process. Cognate receptor gene and protein expression were analyzed with qRT-PCR and immunoblot in primary fibroblasts derived from lung tissues of normal donors (NL) and patients with IPF or SSc. Compared to NL, steady-state receptor gene expression was decreased in SSc but not in IPF. IGF-II stimulation differentially decreased receptor mRNA and protein levels in NL, IPF, and SSc fibroblasts. Neutralizing antibody, siRNA, and receptor inhibition targeting endogenous IGF-II and its primary receptors, type 1 IGF receptor (IGF1R), IGF2R, and insulin receptor (IR) resulted in loss of the IGF-II response. IGF-II tipped the TIMP:MMP balance, promoting a fibrotic environment both intracellularly and extracellularly. Differentiation of fibroblasts into myofibroblasts by IGF-II was blocked with a TGFβ1 receptor inhibitor. IGF-II also increased TGFβ2 and TGFβ3 expression, with subsequent activation of canonical SMAD2/3 signaling. Therefore, IGF-II promoted fibrosis through IGF1R, IR, and IGF1R/IR, differentiated fibroblasts into myofibroblasts, decreased protease production and extracellular matrix degradation, and stimulated expression of two TGFβ isoforms, suggesting that IGF-II exerts pro-fibrotic effects via multiple mechanisms.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic obstructive pulmonary disease (COPD) is a progressive lung disease characterized by abnormal cellular responses to cigarette smoke, resulting in tissue destruction and airflow limitation. ...Autophagy is a degradative process involving lysosomal turnover of cellular components, though its role in human diseases remains unclear.
Increased autophagy was observed in lung tissue from COPD patients, as indicated by electron microscopic analysis, as well as by increased activation of autophagic proteins (microtubule-associated protein-1 light chain-3B, LC3B, Atg4, Atg5/12, Atg7). Cigarette smoke extract (CSE) is an established model for studying the effects of cigarette smoke exposure in vitro. In human pulmonary epithelial cells, exposure to CSE or histone deacetylase (HDAC) inhibitor rapidly induced autophagy. CSE decreased HDAC activity, resulting in increased binding of early growth response-1 (Egr-1) and E2F factors to the autophagy gene LC3B promoter, and increased LC3B expression. Knockdown of E2F-4 or Egr-1 inhibited CSE-induced LC3B expression. Knockdown of Egr-1 also inhibited the expression of Atg4B, a critical factor for LC3B conversion. Inhibition of autophagy by LC3B-knockdown protected epithelial cells from CSE-induced apoptosis. Egr-1(-/-) mice, which displayed basal airspace enlargement, resisted cigarette-smoke induced autophagy, apoptosis, and emphysema.
We demonstrate a critical role for Egr-1 in promoting autophagy and apoptosis in response to cigarette smoke exposure in vitro and in vivo. The induction of autophagy at early stages of COPD progression suggests novel therapeutic targets for the treatment of cigarette smoke induced lung injury.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background The intraoperative use of cardiopulmonary bypass (CPB) in lung transplantation has been associated with increased rates of pulmonary dysfunction and bleeding complications. More recently, ...extracorporeal membrane oxygenation (ECMO) has emerged as a valid alternative method of support and has been our preferred method of support since March 2012. We compared early and midterm outcomes of these 2 support methods. Methods Between July 2007 and April 2013, 271 consecutive patients underwent lung transplant using CPB (n = 222) or ECMO (n = 49). We retrospectively reviewed the outcomes of these patients requiring CPB or ECMO during lung transplant. Results The CPB and ECMO groups had comparable demographic and operative characteristics; however, the ECMO group had higher mean lung allocation scores (73 vs 52, p < 0.001). In the CPB group, more patients required reintubation (35.6% vs 20.4%, p = 0.04) or temporary tracheostomy (44.6% vs 28.6%, p = 0.05). Patients in the CPB group had a higher rate of renal failure requiring dialysis than the ECMO group (22.1% vs 8.2 %, p = 0.028). There were no differences in severe PGD requiring postoperative circulatory support ( p = 0.83) or the need for perioperative red blood cell transfusions ( p = 0.64) between the groups. No differences in 30-day (5% CPB vs 4.1% ECMO) or 6-month mortality (14.4% CPB vs 14.3% ECMO) were noted. Conclusions The use of ECMO in lung transplant is safe and in our experience was associated with decreased rates of pulmonary and renal complications, as compared with CPB. Extracorporeal membrane oxygenation has become our preferred method of intraoperative support during lung transplantation.
Tezacaftor (formerly VX-661) is an investigational small molecule that improves processing and trafficking of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro, and improves ...CFTR function alone and in combination with ivacaftor.
To evaluate the safety and efficacy of tezacaftor monotherapy and of tezacaftor/ivacaftor combination therapy in subjects with cystic fibrosis homozygous for F508del or compound heterozygous for F508del and G551D.
This was a randomized, placebo-controlled, double-blind, multicenter, phase 2 study (NCT01531673). Subjects homozygous for F508del received tezacaftor (10 to 150 mg) every day alone or in combination with ivacaftor (150 mg every 12 h) in a dose escalation phase, as well as in a dosage regimen testing phase. Subjects compound heterozygous for F508del and G551D, taking physician-prescribed ivacaftor, received tezacaftor (100 mg every day).
Primary endpoints were safety through Day 56 and change in sweat chloride from baseline through Day 28. Secondary endpoints included change in percent predicted FEV
(ppFEV
) from baseline through Day 28 and pharmacokinetics. The incidence of adverse events was similar across treatment arms. Tezacaftor (100 mg every day)/ivacaftor (150 mg every 12 h) resulted in a 6.04 mmol/L decrease in sweat chloride and 3.75 percentage point increase in ppFEV
in subjects homozygous for F508del, and a 7.02 mmol/L decrease in sweat chloride and 4.60 percentage point increase in ppFEV
in subjects compound heterozygous for F508del and G551D from baseline through Day 28 (P < 0.05 for all).
These results support continued clinical development of tezacaftor (100 mg every day) in combination with ivacaftor (150 mg every 12 h) in subjects with cystic fibrosis. Clinical trial registered with www.clinicaltrials.gov (NCT01531673).
Pseudomonas aeruginosa
is the most prevalent bacterial species that contribute to cystic fibrosis (CF) respiratory failure. The impaired function of CF transmembrane conductance regulator leads to ...abnormal epithelial Cl
–/
HCO
3
–
transport and acidification of airway surface liquid. However, it remains unclear why the CF lung is most commonly infected by
Pseudomonas aeruginosa
versus other pathogens. We carried out studies to investigate if lower pH helps
Pseudomonas aeruginosa
adapt and thrive in the CF-like acidic lung environment. Our results revealed that
Pseudomonas aeruginosa
generally forms more biofilm, induces antibiotic resistance faster in acidic conditions, and can be reversed by returning the acidic environment to physiologically neutral conditions.
Pseudomonas aeruginosa
appears to be highly adaptive to the CF-like acidic pH environment. By studying the effects of an acidic environment on bacterial response, we may provide a new therapeutic option in preventing chronic
Pseudomonas aeruginosa
infection and colonization.
Background Preoperative extracorporeal membrane oxygenation (ECMO) is a risk factor for poor outcome and currently considered a contraindication to lung transplantation. The lung allocation score ...system was introduced in May 2005 and prioritizes lung allocation to those with the greatest respiratory impairment. The purpose of this study is to determine whether ECMO as a bridge to lung transplantation is an acceptable option to support those in respiratory failure until donor lungs become available in the lung allocation score era. Method A retrospective review of 715 consecutive lung transplants performed between May 2005 and September 2011 was conducted using a prospectively collected institutional registry database. Twenty-four lung transplants (3.4%) were performed in the 31 patients with attempted pretransplant ECMO; 7 patients who received ECMO patients did not survive or were deemed unfit for transplantation. These patients were compared with a control group of 691 patients who did not receive pretransplant ECMO. Results The duration of pretransplant ECMO was 171 ± 242 hours (median, 91 hours). Venovenous ECMO was used for respiratory failure in 15 patients, whereas venoarterial ECMO was used for circulatory collapse due to pulmonary hypertension in 9 patients. Patients in the retransplant ECMO group were younger (46 ± 15 years vs 57 ± 14 years, P < .01) compared with the control group, with no difference in recipient gender (male/female: 10/14 vs 380/311), donor age (33 ± 14 years vs 36 ± 15 years), or donor gender (male/female: 10/14 vs 352/339). Emphysema was less common (1, 4% vs 260, 38%, P < .01), and cystic fibrosis (5, 21% vs 72, 10%, P = .09), redo lung transplant (3, 13% vs 28, 4%, P = .08), and bronchiectasis (2, 8% vs 6, 1%, P = .03) were more common in the pretransplant ECMO group. Patients in the pretransplant ECMO group had a significantly higher lung allocation score (87 ± 9 vs 44 ± 15, P < .01). All patients in the pretransplant ECMO group underwent double lung transplants on pump (cardiopulmonary bypass/ECMO), and single lung transplants were performed in 171 patients (25%) and pump was used in 243 patients (35%) in the control group. The cardiopulmonary bypass time was longer in the pretransplant ECMO group (277 ± 69 minutes vs 225 ± 89 minutes, P = .02), with no difference in ischemic time (343 ± 93 minutes vs 330 ± 98 minutes, P = .54). Cadaveric lobar lung transplants were performed because of the urgency to overcome size mismatch with an oversized donor more frequently in 25% (n = 6, no mortality with the longest follow-up at 6 years) of patients in the pretransplant ECMO group versus 0.3% (n = 2) of patients in the control group ( P < .01). Post-transplant ECMO was used for primary graft dysfunction in 13 patients (54%) in the pretransplant ECMO group and 41 patients (6%) in the control group ( P < .01). The median hospital stay was 46 days in the pretransplant ECMO group versus 27 days in the control group ( P = .16). The actuarial survivals after lung transplants at 1, 3, 6, 12, and 24 months were 96%, 88%, 83%, 74%, and 74%, respectively, in the pretransplant ECMO group, and 97%, 94%, 90%, 83%, and 74%, respectively, in the control group ( P = .787). Conclusions Although the incidence of primary graft dysfunction requiring post-transplant ECMO is higher and the hospital stay is longer in patients receiving pretransplant ECMO, the graft survival is good (2-year survival, 74%). ECMO is efficacious as a bridge to lung transplantation with good post-lung transplant outcomes.
Systemic sclerosis (SSc) is a connective tissue disorder that results in fibrosis of the skin and visceral organs. SSc-associated pulmonary fibrosis (SSc-PF) is the leading cause of death amongst SSc ...patients. Racial disparity is noted in SSc as African Americans (AA) have a higher frequency and severity of disease than European Americans (EA). Using RNAseq, we determined differentially expressed genes (DEGs; q < 0.1, log2FC > |0.6|) in primary pulmonary fibroblasts from SSc lungs (SScL) and normal lungs (NL) of AA and EA patients to characterize the unique transcriptomic signatures of AA-NL and AA-SScL fibroblasts using systems-level analysis. We identified 69 DEGs in "AA-NL vs. EA-NL" and 384 DEGs in "AA-SScL vs. EA-SScL" analyses, and a comparison of disease mechanisms revealed that only 7.5% of DEGs were commonly deregulated in AA and EA patients. Surprisingly, we also identified an SSc-like signature in AA-NL fibroblasts. Our data highlight differences in disease mechanisms between AA and EA SScL fibroblasts and suggest that AA-NL fibroblasts are in a "pre-fibrosis" state, poised to respond to potential fibrotic triggers. The DEGs and pathways identified in our study provide a wealth of novel targets to better understand disease mechanisms leading to racial disparity in SSc-PF and develop more effective and personalized therapies.
BACKGROUND Palliative care, integrated early, may reduce symptom burden in patients with idiopathic pulmonary fibrosis (IPF). However, limited information exists on timing and clinical practice. The ...purpose of this study was to describe the time course of events prior to death in patients with IPF managed at a specialty center with a focus on location of death and timing of referral for palliative care. METHODS Data were retrospectively extracted from the health system's data repository and obituary listings. The sample included all decedents, excluding lung transplant recipients, who had their first visit to the center between 2000 and 2012. RESULTS Median survival for 404 decedents was 3 years from diagnosis and 1 year from first center visit. Of 277 decedents whose location of death could be determined, > 50% died in the hospital (57%). Only 38 (13.7%) had a formal palliative care referral and the majority (71%) was referred within 1 month of their death. Decedents who died in the academic medical center ICU were significantly younger than those who died in a community hospital ward ( P = .04) or hospice ( P = .001). CONCLUSIONS The majority of patients with IPF died in a hospital setting and only a minority received a formal palliative care referral. Referral to palliative care occurred late in the disease. These findings indicate the need to study adequacy of end-of-life management in IPF and promote earlier discussion and referral to palliative care.
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