Soma Jyothula MD FCCP

BACKGROUND:
The objective of this study was to examine combined prognostic influence of body mass index (BMI) and SMWD on mortality in lung transplant recipients.
METHODS:
Consecutive isolated lung transplant recipients were identified. Preoperative BMI and SMWD data were collected. The cohort was followed for all-cause mortality.
RESULTS:
The study included 324 lung transplant recipients with mean age of 57 ± 13 years and 58% were male (27% obstructive, 3% vascular, 6% cystic… Show more

BACKGROUND:
The objective of this study was to examine combined prognostic influence of body mass index (BMI) and SMWD on mortality in lung transplant recipients.
METHODS:
Consecutive isolated lung transplant recipients were identified. Preoperative BMI and SMWD data were collected. The cohort was followed for all-cause mortality.
RESULTS:
The study included 324 lung transplant recipients with mean age of 57 ± 13 years and 58% were male (27% obstructive, 3% vascular, 6% cystic fibrosis, and 64% with restrictive lung diseases). In the total cohort; 37% had normal BMI, 10% were underweight, 33% were overweight, and 20% were obese. The median SMWD was 700 feet. The lower SMWDgroup was defined as the patients who had SMWD <237 feet as determined by receiver operating characteristic (ROC). Based on this definition, 66 patients (20%) had lower SMWD. There were 71 deaths during a median follow-up of 2.3 years. In multivariate analysis, both BMI and SMWD were independently associated with death. Being overweight was associated with reduced mortality risk (hazard ratio (HR) 0.50, P = 0.042) compared to the normal BMI group, and this was primarily driven by early mortality posttransplant. This paradoxical overweight-mortality relationship remained significant in the lower SMWD group (HR 0.075, P = 0.018), but not in the higher SMWD group (P = 0.552).
CONCLUSION:
In lung transplant recipients under lung allocation score (LAS) era, pretransplant BMI and SMWD were independent predictors for mortality after the transplant. The lowest mortality risk was noted in a group of transplant recipients identified as overweight; whereas, being underweight or obese was associated with increased mortality. Show less

Patients with end-stage lung disease complicated by cirrhosis are not expected to survive lung transplantation alone. Such patients are potential candidates for combined lung-liver transplantation (CLLT), however few reports document the indications and outcomes after CLLT. This is a review of a large single-center CLLT series. Eight consecutive CLLT performed during 2009-2012 were retrospectively reviewed. One patient received a third simultaneous heart transplant. Mean age was 42.5 ± 11.5… Show more

Patients with end-stage lung disease complicated by cirrhosis are not expected to survive lung transplantation alone. Such patients are potential candidates for combined lung-liver transplantation (CLLT), however few reports document the indications and outcomes after CLLT. This is a review of a large single-center CLLT series. Eight consecutive CLLT performed during 2009-2012 were retrospectively reviewed. One patient received a third simultaneous heart transplant. Mean age was 42.5 ± 11.5 years. Pulmonary indications included cystic fibrosis (CF) (n = 3), idiopathic pulmonary fibrosis (n = 2), α1-antitrypsin deficiency (AATD) (n = 1) and pulmonary hypertension (n = 2). Liver indications were CF (n = 3), hepatitis C (n = 2), AATD (n = 1), cryptogenic (n = 1), and cardiac/congestive (n = 1). Urgency was reflected by median lung allocation score (LAS) of 41 (36.0-89.0) and median predicted FEV1 of 25.7%. Median donor age was 25 (20-58) years with median cold ischemia times of 147 minutes and 6.1 hours for lung and liver, respectively. Overall patient survival at 30 days, 90 days and 1 year was 87.5%, 75.0% and 71.4% respectively. One patient had evidence of acute lung rejection, and no patients had liver allograft rejection. Early postoperative mortalities (90 days) were caused by sepsis in 2 recipients who exhibited the highest LAS of 69.9 and 89.0. The remaining recipients had a median LAS of 39.5 and 100% survival at 1-year. Median length of stay was 25 days (7-181). Complications requiring operative intervention included bile duct ischemia (n = 1) and bile leak (n = 1), ischemia of the bronchial anastomosis (n = 1), and necrotizing pancreatitis with duodenal perforation (n = 1). This series reflects a large single-center CLLT experience. Sepsis is the most common cause of death. The procedure should be considered for candidates with LAS < 50. Liver Transpl 20:46-53, 2014. © 2013 AASLD. Show less

Rationale: IL-4Rα, the common receptor component for IL-4 and IL-13, plays a critical role in IL-4- and IL-13-mediated signaling pathways that regulate airway inflammation and remodeling. However, the regulatory mechanisms underlying IL-4Rα turnover and its signal termination remain elusive. Objectives: To evaluate the role of STUB1 (STIP1 homology and U-Box containing protein 1) in regulating IL-4R signaling in airway inflammation. Methods: The roles of STUB1 in IL-4Rα degradation and its… Show more

Rationale: IL-4Rα, the common receptor component for IL-4 and IL-13, plays a critical role in IL-4- and IL-13-mediated signaling pathways that regulate airway inflammation and remodeling. However, the regulatory mechanisms underlying IL-4Rα turnover and its signal termination remain elusive. Objectives: To evaluate the role of STUB1 (STIP1 homology and U-Box containing protein 1) in regulating IL-4R signaling in airway inflammation. Methods: The roles of STUB1 in IL-4Rα degradation and its signaling were investigated by immunoblot, immunoprecipitation, and flow cytometry. The involvement of STUB1 in airway inflammation was determined in vivo by measuring lung inflammatory cells infiltration, mucus production, serum lgE levels, and alveolar macrophage M2 activation in STUB1(-/-) mice. STUB1 expression was evaluated in airway epithelium of patients with asthma and lung tissues of subjects with chronic obstructive pulmonary disease. Measurements and Main Results: STUB1 interacted with IL-4Rα and targeted it for ubiquitination-mediated proteasomal degradation, terminating IL-4 or IL-13 signaling. STUB1 knockout cells showed increased levels of IL-4Rα and sustained STAT6 activation, whereas STUB1 overexpression reduced IL-4Rα levels. Mice deficient in STUB1 had spontaneous airway inflammation, alternative M2 activation of alveolar macrophage, and increased serum IgE. STUB1 levels were increased in airways of subjects with asthma or chronic obstructive pulmonary disease, suggesting that up-regulation of STUB1 might be an important feedback mechanism to dampen IL-4R signaling in airway inflammation. Conclusions: Our study identified a previously uncharacterized role for STUB1 in regulating IL-4R signaling, which might provide a new strategy for attenuating airway inflammation. Show less

PURPOSE OF REVIEW:
Asthma is a common worldwide respiratory illness with significant morbidity and mortality. The disease is characterized by airway inflammation with involvement of multiple biological pathways. Genetic predisposition and increased susceptibility to severe respiratory viral infections are well known clinical features of asthma. Autophagy is an evolutionarily conserved cellular degradation process with significant impact on immunity and antiviral response. In this review we… Show more

PURPOSE OF REVIEW:
Asthma is a common worldwide respiratory illness with significant morbidity and mortality. The disease is characterized by airway inflammation with involvement of multiple biological pathways. Genetic predisposition and increased susceptibility to severe respiratory viral infections are well known clinical features of asthma. Autophagy is an evolutionarily conserved cellular degradation process with significant impact on immunity and antiviral response. In this review we have described the role of autophagy in immune cell survival, proliferation and function. Autophagy has complex effects on immune response involved in inflammation, specifically Th2 immune response. Common respiratory viruses are associated with increased morbidity and mortality in asthmatic patients.
RECENT FINDINGS:
We describe recent studies showing the effect of autophagy on replication and immune response to common respiratory viruses. The role of autophagy in asthma has recently been investigated. Two studies have been published describing the association of autophagy with asthma. Genetic polymorphism in specific autophagy genes is associated with asthma and influences gene expression in an experimental in-vivo model.
SUMMARY:
These studies provide us with a window into the possible role of autophagy in asthma and offer new clues to pathogenesis. Modulation of autophagy has the potential to develop into a new therapeutic avenue to treat this common respiratory ailment.
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RATIONALE AND OBJECTIVE:
Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated.
METHODS:
Using genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging… Show more

RATIONALE AND OBJECTIVE:
Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated.
METHODS:
Using genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP.
MEASUREMENTS AND MAIN RESULTS:
We demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively). In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p<0.05). We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls.
CONCLUSION:
Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. These results provide novel evidence for a role for ATG5 in childhood asthma. Show less

Pulmonary hypertension (PH) is the hemodynamic manifestation of various pathological processes that result in elevated pulmonary artery pressures (PAP). The National Institutes of Health Registry defined pulmonary arterial hypertension as the mean PAP of more than 25 mm Hg with a pulmonary capillary wedge pressure or left atrial pressure equal to or less than 15 mm Hg. This definition remains the currently accepted definition of PH that is used to define PH related to multiple clinical… Show more

Pulmonary hypertension (PH) is the hemodynamic manifestation of various pathological processes that result in elevated pulmonary artery pressures (PAP). The National Institutes of Health Registry defined pulmonary arterial hypertension as the mean PAP of more than 25 mm Hg with a pulmonary capillary wedge pressure or left atrial pressure equal to or less than 15 mm Hg. This definition remains the currently accepted definition of PH that is used to define PH related to multiple clinical conditions including chronic obstructive pulmonary disease (COPD). The estimated US prevalence of COPD by the National Health Survey in 2002 in people aged >25 was 12.1 million. There is a lack of large population-based studies in COPD to document the correct prevalence of PH and outcome. The major cause of PH in COPD is hypoxemia leading to vascular remodeling. Echocardiogram is the initial screening tool of choice for PH. This simple noninvasive test can provide an estimate of right ventricular systolic and right atrial pressures. Right heart catheterization remains the gold standard to diagnose PH. It provides accurate measurement of mean PAP and pulmonary capillary wedge pressure. Oxygen therapy remains the cornerstone therapeutic for hypoxemia in COPD patients. Anecdotal reports suggest utility of PDE5-inhibitors and prostacyclin to treat COPD-related PH. Large randomized clinical trials are needed before the use of these drugs can be recommended Show less