Stephen Kirkby

MiR-101 and miR-144 Regulate the Expression of the CFTR Chloride Channel in the Lung

The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride channel that plays a critical role in the lung by maintaining fluid homeostasis. Absence or malfunction of CFTR leads to Cystic Fibrosis, a disease characterized by chronic infection and inflammation. We recently reported that air pollutants such as cigarette smoke and cadmium negatively regulate the expression of CFTR by affecting several steps in the biogenesis of CFTR protein. MicroRNAs (miRNAs) have recently received a great deal of attention as both biomarkers and therapeutics due to their ability to regulate multiple genes. Here, we show that cigarette smoke and cadmium up-regulate the expression of two miRNAs (miR-101 and miR-144) that are predicted to target CFTR in human bronchial epithelial cells. When premature miR-101 and miR-144 were transfected in human airway epithelial cells, they directly targeted the CFTR 3′UTR and suppressed the expression of the CFTR protein. Since miR-101 was highly up-regulated by cigarette smoke in vitro, we investigated whether such increase also occurred in vivo. Mice exposed to cigarette smoke for 4 weeks demonstrated an up-regulation of miR-101 and suppression of CFTR protein in their lungs. Finally, we show that miR-101 is highly expressed in lung samples from patients with severe chronic obstructive pulmonary disease (COPD) when compared to control patients. Taken together, these results suggest that chronic cigarette smoking up-regulates miR-101 and that this miRNA could contribute to suppression of CFTR in the lungs of COPD patients.

Pulmonary Hypertension in Cystic Fibrosis with Advanced Lung Disease

RATIONALE The impact of pulmonary hypertension (PH) on survival in cystic fibrosis (CF) remains unclear. OBJECTIVES To determine the influence of PH on survival in the CF population. METHODS The United Network for Organ Sharing database was queried from 1987 to 2013 to identify first-time lung transplant candidates who were tracked from wait list entry date until death or censoring to determine influence of PH. Using right heart catheterization measurements, mild PH was defined as mean pulmonary artery pressure greater than or equal to 25 mm Hg and severe greater than or equal to 35 mm Hg. MEASUREMENTS AND MAIN RESULTS Of 2,781 CF patients, 2,100 were used for univariate analysis, 764 for Kaplan-Meier survival function, 687 for multivariate Cox models, and 576 and 132 for matching on the propensity of mild PH and severe PH, respectively. Univariate Cox analysis found significant differences in survival for mild PH (hazard ratio [HR], 1.747; 95% confidence interval [CI], 1.387-2.201; P < 0.001) and severe PH (HR, 2.299; 95% CI, 1.639-3.225; P < 0.001). Further assessment by multivariate Cox models identified significant risk for death associated with mild PH (HR, 1.757; 95% CI, 1.367-2.258; P < 0.001) and severe PH (HR, 2.284; 95% CI, 1.596-3.268; P < 0.001). Cox regression stratified on matched pairs of PH cases and control subjects confirmed the risk for death for mild PH (HR, 1.919; 95% CI, 1.290-2.85; P = 0.001) and severe PH (HR, 4.167; 95% CI, 1.709-10.157; P = 0.002). CONCLUSIONS The manifestation of PH is associated with significantly increased risk for death in CF patients with advanced lung disease.

Pediatric lung transplantation: indications and outcomes

Lung transplantation (LTx) is a treatment option for infants and children with untreatable and otherwise fatal pulmonary diseases. To date, over 1,800 lung transplants have been performed, most frequently in children over the age of five years. The most common indications for transplantation in children overall are cystic fibrosis (CF) and idiopathic pulmonary hypertension (PH). The surfactant protein deficiencies, other interstitial lung diseases (ILDs), and congenital heart disease are important indications among young children and infants. Re-transplantation is an option for selected recipients with chronic allograft rejection. Overall survival following pediatric LTx is similar to that encountered in adult patients, with recent registry data indicating a median survival of 4.9 years. Other outcomes such as the incidence of bronchiolitis obliterans (BO) and the presence of key post-transplant co-morbid conditions are also similar to the experience in adult lung transplant recipients.

Impact of pulmonary hypertension on survival in patients with cystic fibrosis undergoing lung transplantation: An analysis of the UNOS registry

BACKGROUND Pulmonary hypertension (PH) is a comorbidity reported in patients with cystic fibrosis (CF) with research limited to single-center studies. METHODS To assess the impact of PH in patients with CF who received a lung transplant (LTx), the United Network for Organ Sharing was queried from 1987 to 2012, restricting analysis to transplant patients 6-55 years old between 1/1/2005 and 7/6/2011. RESULTS Of 23,951 lung transplants, 1177 met inclusion criteria with 831 having mean pulmonary artery pressure (mPAP) data available. For the entire cohort, mean age was 30.3 (SD=9.2, range 12-55), and mean mPAP was 26.5 (SD = 7.8, range 5-66) mmHg. A total of 470 (57%) had PH defined as mPAP ≥ 25 mmHg. Comparing PH to non-PH groups, mean forced expiratory volume in one second (FEV1) was 24.4 (SD = 13.8) vs. 26 (SD=13.9) % of predicted, mean supplemental oxygen requirement at rest was 4.5 (SD = 4.1) vs. 3.7 (SD = 3.0) liters per minute, and mean lung allocation score was 49 (SD = 16) vs. 43 (SD = 12), respectively. For the PH group, median survival was 84.4 months compared to 67.1 months for the non-PH group (log-rank p-value = 0.326). The adjusted hazard ratio for PH vs. non-PH was 0.862 (95% CI: 0.653-1.138; p = 0.293), thus indicating no statistically significant effect of PH on survival. CONCLUSIONS A high prevalence of PH was found in CF patients prior to LTx. Based on our models despite PH being prevalent, there is no strong evidence suggesting that it significantly alters the risk of death in CF patients after LTx.

To induce or not to induce: a 21st century evaluation of lung transplant immunosuppression's effect on survival

The impact of induction immunosuppression on long‐term survival in lung transplant recipients remains unclear. We sought to evaluate the effect of contemporary induction immunosuppression agents in lung transplant recipients’ survival, utilizing national registry data.

Update on antibiotics for infection control in cystic fibrosis

Cystic fibrosis pulmonary disease is characterized by chronic and recurrent infection, airway inflammation, bronchiectasis and progressive obstructive lung physiology. Advances in the treatment of common airway pathogens such as Pseudomonas aeruginosa have led to a marked improvement in overall survival. However, antibiotic treatment options are often limited by multidrug resistance, potential toxicities and treatment burden to individual patients. While appropriate anti-infective therapy reduces bacterial density in the airways and may result in clinical improvement, true eradication of airway infection is seldom achieved except for early-stage infections. This review summarizes current approaches for acute and chronic anti-infective therapy in cystic fibrosis.

Effect of pulmonary hypertension on survival in patients with idiopathic pulmonary fibrosis after lung transplantation: An analysis of the United Network of Organ Sharing registry

BACKGROUND Pulmonary hypertension (PH) is a comorbidity associated with idiopathic pulmonary fibrosis (IPF). There is limited research regarding the effect on survival after lung transplantation (LTx). METHODS To assess the effect of PH on survival in patients with IPF who received LTx, the United Network for Organ Sharing was queried for eligible patients with recorded mean (PAmean) and systolic (PAsystolic) pulmonary artery pressure. The analysis was restricted to the post-lung allocation scoring system starting May 1, 2005, to provide a cohort receiving present-day therapies and management. The last update of the data set was July 6, 2012, so a cutoff date of July 6, 2011, was chosen to allow for the possibility of at least 1 year of follow-up. Thresholds of ≥25 and ≥35 mm Hg were chosen for PAmean and PAsystolic, respectively, as indicators of PH. RESULTS Of 23,951 LTxs in the UNOS data set, 2,542 met inclusion criteria, 1,234 (49%) with PAmean ≥ 25 mm Hg and 1,680 (66%) with PAsystolic ≥ 35 mm Hg. PAmean and PAsystolic were highly correlated, with an estimated correlation coefficient ρ = 0.93 (p < 0.001). Patients with PH (PAmean ≥ 25 mm Hg or PAsystolic ≥ 35 mm Hg) tended to have higher ischemic times, lung allocation score values, forced vital capacity percentage predicted at LTx, and supplemental oxygen requirement at rest values. In addition, a larger proportion of patients with PH was African American, male, had diabetes, and received bilateral LTx compared with single LTx. Comparing PAmean < 25 vs ≥ 25 mm Hg and PAsystolic < 35 vs ≥ 35 mm Hg, median survival in months was 60.4 (95% confidence interval [CI], 55.2-80.4) vs 61.4 (95% CI, 56.9-66.9; log-rank p = 0.876) and 57.6 (95% CI, 50.9-68.0) vs 64.3 (95% CI, 57.5-71.3; log-rank p = 0. 247), respectively. Hazard ratios for both definitions of PH from univariable and multivariable Cox proportional hazard models were close to 1 and none were statistically significant. CONCLUSIONS On the basis of our models and despite PH being prevalent, there is no strong evidence suggesting that PH significantly alters the risk of death in IPF patients after LTx.

Reduction of lipid‐laden macrophage index after laparoscopic Nissen fundoplication in cystic fibrosis patients after lung transplantation

Lipid‐laden macrophage (LLM) index could be potentially useful in assessing gastroesophageal (GE) reflux and aspiration after lung transplantation (LT) in patients with cystic fibrosis (CF).

Active rehabilitation with venovenous extracorporeal membrane oxygenation as a bridge to lung transplantation in a pediatric patient

BackgroundActive physical rehabilitation while bridged to lung transplantation with venovenous (VV) extracorporeal membrane oxygenation (ECMO) is an evolving treatment option in adults with limited published experience in pediatric patients.MethodsThe administration of VV ECMO through the placement of a single-site bicaval dual-lumen (BCDL) catheter (Avalon Laboratories, Rancho Dominguez, CA, USA) permits respiratory support in a critically ill patient with avoidance of sedation and paralytics while allowing rehabilitation and oral nutrition.ResultsA 13-year-old girl with advanced interstitial lung disease underwent active rehabilitation while being bridged to lung transplantation with single-site VV ECMO.ConclusionsThe innovative use of single-site VV ECMO with a BCDL catheter is transforming the care of adult patients with advanced lung disease and acute respiratory failure as a method to extend the life of a lung transplantation candidate to maximize all opportunities for organ availability. Based on our experiences, clinicians caring for children should be aware of this potential option in pediatric patients requiring lung transplantation.

Aztreonam (for inhalation solution) for the treatment of chronic lung infections in patients with cystic fibrosis: an evidence-based review.

Cystic fibrosis (CF) is a genetic disease caused by abnormal chloride transport across cellular membranes. In the respiratory tract, this molecular defect causes obstruction of the airways by mucus and chronic endobronchial infection. The majority of patients suffer early death from chronic respiratory disease. Pseudomonas aeruginosa is the predominant chronic airway pathogen in older children and adults with CF and is associated with worse outcomes. However, overall survival in CF has been greatly improved in recent decades due in large part to the aggressive treatment of chronic infections such as P. aeruginosa. While intravenous and oral antibiotics are commonly used in the management of CF respiratory infections, inhaled anti-infective therapies offer the benefit of delivering the drug directly to the site of infection and avoiding potential toxicities associated with systemic absorption. Aztreonam lysine (AZLI) has recently been developed as an inhaled antibiotic for chronic use in CF patients with endobronchial P. aeruginosa infection. This paper reviews background data and the clinical studies which contributed to AZLI’s formal FDA approval and growing role in the management of CF pulmonary disease.