Respiratory impairments in patients suffering from Fabry disease - A cross-sectional study.

BACKGROUND: The inherited X-linked disorder, Fabry disease, is caused by deficient lysosomal enzyme α-galactosidase A, with progressive accumulation of globotriaosylceramide in multiple organs including the upper and lower airways. OBJECTIVES: To assess pulmonary function at the time of the first pulmonary function test (PFT) performed among the National Danish Fabry cohort and define the prevalence of affected lung function variables. MATERIALS AND METHOD: A cross-sectional retrospective cohort study of 86 adult patients enrolled in one or both international patient registry databases for Fabry disease, Fabry Registry or FollowME with at least one PFT. The Mainz Severity Score Index (MSSI) was calculated to determine the disease severity. Lung function variables were examined by multivariate regression adjusted for important variables for developing airway illness. RESULTS: Seventeen patients (20%) showed obstructive airflow limitation and 7 (8%) a restrictive lung deficiency. Smoking status (p = .016) and MSSI (p < .001) were associated with increasing obstructive airway limitation. CONCLUSION: The prevalence of affected lung function among the National Danish Fabry cohort was 28%. Patients with classic gene variants frequently developed a decrease in lung function regardless of their smoking status, with significant relationship with disease severity.

Small-Molecule Activation of Protein Phosphatase 2A Counters Bleomycin-Induced Fibrosis in Mice.

The activity of protein phosphatase 2A (PP2A), a serine-threonine phosphatase, is reduced in the lung fibroblasts of idiopathic pulmonary fibrosis (IPF) patients. The objective of this study was to determine whether the reactivation of PP2A could reduce fibrosis and preserve the pulmonary function in a bleomycin (BLM) mouse model. Here, we present a new class of direct small-molecule PP2A activators, diarylmethyl-pyran-sulfonamide, exemplified by ATUX-1215. ATUX-1215 has improved metabolic stability and bioavailability compared to our previously described PP2A activators. Primary human lung fibroblasts were exposed to ATUX-1215 and an older generation PP2A activator in combination with TGFß. ATUX-1215 treatment enhanced the PP2A activity, reduced the phosphorylation of ERK and JNK, and reduced the TGFß-induced expression of ACTA2, FN1, COL1A1, and COL3A1. C57BL/6J mice were administered 5 mg/kg ATUX-1215 daily following intratracheal instillation of BLM. Three weeks later, forced oscillation and expiratory measurements were performed using the Scireq Flexivent System. ATUX-1215 prevented BLM-induced lung physiology changes, including the preservation of normal PV loop, compliance, tissue elastance, and forced vital capacity. PP2A activity was enhanced with ATUX-1215 and reduced collagen deposition within the lungs. ATUX-1215 also prevented the BLM induction of Acta2, Ccn2, and Fn1 gene expression. Treatment with ATUX-1215 reduced the phosphorylation of ERK, p38, JNK, and Akt and the secretion of IL-12p70, GM-CSF, and IL1α in BLM-treated animals. Delayed treatment with ATUX-1215 was also observed to slow the progression of lung fibrosis. In conclusion, our study indicates that the decrease in PP2A activity, which occurs in fibroblasts from the lungs of IPF subjects, could be restored with ATUX-1215 administration as an antifibrotic agent.

Evaluating Novel Protein Phosphatase 2A Activators as Therapeutics for Emphysema.

The activity of PP2A (protein phosphatase 2A), a serine-threonine phosphatase, is reduced by chronic cigarette smoke (SM) exposure and α-1 antitrypsin (AAT) deficiency, and chemical activation of PP2A reduces the loss of lung function in SM-exposed mice. However, the previously studied PP2A-activator tricyclic sulfonamide compound DBK-1154 has low stability to oxidative metabolism, resulting in fast clearance and low systemic exposure. Here we compare the utility of a new more stable PP2A activator, ATUX-792, versus DBK-1154 for the treatment of SM-induced emphysema. ATUX-792 was also tested in human bronchial epithelial cells and a mouse model of AAT deficiency, Serpina1a-e-knockout mice. Human bronchial epithelial cells were treated with ATUX-792 or DBK-1154, and cell viability, PP2A activity, and MAP (mitogen-activated protein) kinase phosphorylation status were examined. Wild-type mice received vehicle, DBK-1154, or ATUX-792 orally in the last 2 months of 4 months of SM exposure, and 8-month-old Serpina1a-e-knockout mice received ATUX-792 daily for 4 months. Forced oscillation and expiratory measurements and histology analysis were performed. Treatment with ATUX-792 or DBK-1154 resulted in PP2A activation, reduced MAP kinase phosphorylation, immune cell infiltration, reduced airspace enlargements, and preserved lung function. Using protein arrays and multiplex assays, PP2A activation was observed to reduce AAT-deficient and SM-induced release of CXCL5, CCL17, and CXCL16 into the airways, which coincided with reduced neutrophil lung infiltration. Our study indicates that suppression of the PP2A activity in two models of emphysema could be restored by next-generation PP2A activators to impact lung function.

The Relationship of Cholesterol Responses to Mitochondrial Dysfunction and Lung Inflammation in Chronic Obstructive Pulmonary Disease.

Hyperlipidemia is frequently reported in chronic obstructive pulmonary disease (COPD) patients and is linked to the progression of the disease and its comorbidities. Hypercholesterolemia leads to cholesterol accumulation in many cell types, especially immune cells, and some recent studies suggest that cholesterol impacts lung epithelial cells' inflammatory responses and mitochondrial responses. Several studies also indicate that targeting cholesterol responses with either statins or liver X receptor (LXR) agonists may be plausible means of improving pulmonary outcomes. Equally, cholesterol metabolism and signaling are linked to mitochondrial dysfunction and inflammation attributed to COPD progression. Here, we review the current literature focusing on the impact of cigarette smoke on cholesterol levels, cholesterol efflux, and the influence of cholesterol on immune and mitochondrial responses within the lungs.

Mechanisms Linking COPD to Type 1 and 2 Diabetes Mellitus: Is There a Relationship between Diabetes and COPD?

Chronic obstructive pulmonary disease (COPD) patients frequently suffer from multiple comorbidities, resulting in poor outcomes for these patients. Diabetes is observed at a higher frequency in COPD patients than in the general population. Both type 1 and 2 diabetes mellitus are associated with pulmonary complications, and similar therapeutic strategies are proposed to treat these conditions. Epidemiological studies and disease models have increased our knowledge of these clinical associations. Several recent genome-wide association studies have identified positive genetic correlations between lung function and obesity, possibly due to alterations in genes linked to cell proliferation; embryo, skeletal, and tissue development; and regulation of gene expression. These studies suggest that genetic predisposition, in addition to weight gain, can influence lung function. Cigarette smoke exposure can also influence the differential methylation of CpG sites in genes linked to diabetes and COPD, and smoke-related single nucleotide polymorphisms are associated with resting heart rate and coronary artery disease. Despite the vast literature on clinical disease association, little direct mechanistic evidence is currently available demonstrating that either disease influences the progression of the other, but common pharmacological approaches could slow the progression of these diseases. Here, we review the clinical and scientific literature to discuss whether mechanisms beyond preexisting conditions, lifestyle, and weight gain contribute to the development of COPD associated with diabetes. Specifically, we outline environmental and genetic confounders linked with these diseases.

Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is recognized as a disease of accelerated lung aging. Over the past two decades, mounting evidence suggests an accumulation of senescent cells within the lungs of patients with COPD that contributes to dysregulated tissue repair and the secretion of multiple inflammatory proteins, termed the senescence-associated secretory phenotype (SASP). Cellular senescence in COPD is linked to telomere dysfunction, DNA damage, and oxidative stress. This review gives an overview of the mechanistic contributions and pathologic consequences of cellular senescence in COPD and discusses potential therapeutic approaches targeting senescence-associated signaling in COPD.

Misconceptions concerning maternal and child health in low socioeconomic status societies.

This cross-sectional questionnaire-based study was conducted in order to assess the frequency of misconceptions present in societies of low socioeconomic status so that healthcare providers can pay due attention to whichever misconceptions are most prevalent and work towards eradicating them. The study was conducted in Sultanabad and Rehri Goth areas of Karachi, both being of low socioeconomic status. A sample size of 75 interviewees from each settlement was taken and data collected over the time period of one month. The results indicated that a high frequency of misconceptions is prevalent in societies of low socioeconomic status, where the literacy rates were low.

Surgical lung biopsy in patients with hematological malignancy or hematopoietic stem cell transplantation and unexplained pulmonary infiltrates: improved outcome with specific diagnosis.

Using a retrospective review of medical records, we sought the findings of surgical lung biopsy (SLB) in patients with hematological malignancy or hematopoietic stem cell transplantation (HSCT) and unexplained pulmonary infiltrates and to determine the impact of this procedure on management and outcome of these patients. Sixty-two patients who underwent SLB were evaluated; 31 patients had underlying hematological malignancy and 31 patients were HSCT recipients; 58% of whom underwent allogeneic HSCT. Thirty-three patients (53%) had focal infiltrates on chest CT scan while 29 (47%) had diffuse infiltrates. Thirteen patients were mechanically ventilated prior to SLB, and 27 (43%) were neutropenic. There were 66 diagnoses in the 62 patients, 44 (67%) were specific and 22 (33%) were nonspecific. The most common specific diagnoses were infection (29%), malignancy (27%), and inflammatory conditions (11%). Aspergillosis was the most common diagnosis of all biopsies (21%). SLB led to a change in therapy in 40% of patients and was associated with complications in 7 patients (11%). Specific diagnosis was more likely to lead to a change in therapy (48% vs. 27%, P = 0.06) and was associated with a lower mortality when compared to a nonspecific finding (30% vs. 59%, P = 0.02). Nonspecific diagnosis, on the other hand, was seen more in patients on mechanical ventilation prior to SLB compared to those off mechanical ventilation (69% vs. 27%, P = 0.02). SLB provides a specific diagnosis in the majority of patients with hematologic malignancy or HSCT recipients and unexplained pulmonary infiltrates. Specific diagnosis is more likely to lead to a change in therapy and is associated with a better outcome.

Outcome and prognostic factors of hematopoietic stem cell transplantation recipients admitted to a medical ICU.

OBJECTIVE: To assess the outcome of adult hematopoietic stem cell transplantation (HSCT) recipients who were admitted to a medical ICU (MICU), and to identify the measurable predictors of their MICU outcome. DESIGN: Retrospective chart review study. SETTING: MICU in a tertiary care, university-affiliated medical center with a comprehensive cancer program. PATIENTS: Consecutive adult HSCT recipients admitted to the MICU between January 1998 and June 2001. MEASUREMENTS AND MAIN RESULTS: Eighty-five patients were admitted to the MICU, representing 11.4% of patients who had undergone HSCT during the study period. The mean (+/- SD) age at MICU admission was 46.6 +/- 11.4 years (women, 67%; men, 33%). Forty-five patients (53%) underwent allogeneic HSCT, and 40 patients (47%) underwent autologous HSCT. Fifty-one patients (60%) required mechanical ventilation (MV). Fifty-two patients (61%) survived their MICU stay, and 35 patients (41%) were discharged alive from the hospital. The long-term survival rate (ie, > 6 months) in this cohort was 28%. Nineteen mechanically ventilated patients (37%) survived their MICU stay, and 33 patients (97%) survived who did not require MV (p < 0.01). The independent predictors of poor outcome during the MICU stay were elevated serum lactate level on admission to the MICU, the need for MV, and the presence of more than two organ systems that failed. CONCLUSIONS: The study showed short-term and long-term survival rates among adult HSCT recipients who had been admitted to MICU that were higher than those previously reported. While there were no absolute predictors of mortality, patients with higher MICU admission serum lactate levels, those requiring MV, or those developing more than two organ system failures had poor MICU outcomes.