SH2 Domain-Containing Phosphatase-SHP2 Attenuates Fibrotic Responses through Negative Regulation of Mitochondrial Metabolism in Lung Fibroblasts.

BACKGROUND: We have previously shown that SHP2 downregulation may predispose fibroblasts to differentiate into myofibroblasts and proposed a role for SHP2 downregulation in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Recent data have shown that SHP2 localizes to the mitochondrial intercristae, and its overexpression enhances mitochondrial metabolism leading to oxidative stress and senescence. OBJECTIVE: To determine the effect of SHP2 on fibrotic responses. METHODS AND RESULTS: Primary mouse lung fibroblasts derived from mice carrying a conditional knock-in mutation (D61G/+), rendering the SHP2 catalytic domain constitutively active, had reduced proliferation (1.6-fold, p < 0.05), migration (2-fold, p < 0.05), as well as reduced responsiveness of TGFB-1 induced fibroblasts-to-myofibroblasts differentiation, compared to wild-type ones. Electron microscope analysis revealed that SHP2 D61G/+ mouse lung fibroblasts were characterized by mitochondrial abnormalities, including swollen mitochondria with disrupted electron-lucent cristae and an increased number of autophagosomes compared to wild-type ones. SHP2 D61G/+ MLFs exhibited increased protein levels of autophagy markers, including LC3B-II and p-62, evidence that was confirmed by immunofluorescence analysis. Mitochondrial function analysis revealed that stable (genotype D61G/+) overexpression of SHP2 led to impaired mitochondrial function, as assessed by decreased mitochondrial membrane potential (1.29-fold, p < 0.05), coupling efficiency (1.82 fold, p < 0.05), oxygen consumption rate (1.9-fold, p < 0.05), and increased reactive oxygen species production both at baseline (1.75-fold, p < 0.05) and following H2O2 stimulation (1.63-fold, p < 0.05) compared to wild-type ones (SHP2+/+). SHP2 D61G/+ mouse lung fibroblasts showed enhanced AMPK activity, as well as decreased activation of the mTORC1 signaling pathway, potentially leading to ineffective mitochondrial metabolism and increased autophagy. CONCLUSIONS: SHP2 attenuates fibrotic responses in fibroblast cell lines through negative regulation of mitochondrial metabolism and induction of autophagy. SHP2 activation may represent a promising therapeutic strategy for patients with fibrotic lung diseases.

Reduction in Hospitalizations for Respiratory Diseases during the First COVID-19 Wave in Greece.

INTRODUCTION: During the first COVID-19 wave, a considerable decline in hospital admissions was observed worldwide. AIM: This retrospective cohort study aimed to assess if there were any changes in the number of patients hospitalized for respiratory diseases in Greece during the first CO-VID-19 wave. METHODS: In the present study, we evaluated respiratory disease hospitalization rates across 9 tertiary hospitals in Greece during the study period (March-April 2020) and the corresponding period of the 2 previous years (2018-2019) that served as the control periods. Demographic data and discharge diagnosis were documented for every patient. RESULTS: Of the 1,307 patients who were hospitalized during the study period, 444 (35.5%) were males with a mean (±SD) age of 66.1 ± 16.6 years. There was a 47 and 46% reduction in all-cause respiratory morbidity compared to the corresponding periods of 2018 and 2019, respectively. The mean incidence rate for respiratory diseases during the study period was 21.4 admissions per day, and this rate was significantly lower than the rate during the same period in 2018 (40.8 admissions per day; incidence rate ratio [IRR], 0.525; 95% confidence interval [CI], 0.491-0.562; p < 0.001) or the rate during 2019 (39.9 admissions per day; IRR, 0.537; 95% CI, 0.502-0.574; p < 0.001). The greatest reductions (%) in the number of daily admissions in 2020 were observed for sleep apnoea (87% vs. 2018 and 84% vs. 2019) followed by admissions for asthma (76% vs. 2018 and 79% vs. 2019) and chronic obstructive pulmonary disease (60% vs. 2018 and 51% vs. 2019), while the lowest reductions were detected in hospitalizations for pulmonary embolism (6% vs. 2018 and 23% vs. 2019) followed by tuberculosis (25% vs. both 2018 and 2019). DISCUSSION/CONCLUSION: The significant reduction in respiratory admissions in 2020 raises the reasonable question of whether some patients may have avoided seeking medical attention during the COVID-19 pandemic and suggests an urgent need for transformation of healthcare systems during the pandemic to offer appropriate management of respiratory diseases other than COVID-19.

Computed tomography cephalometric and upper airway measurements in patients with OSA and erectile dysfunction.

PURPOSE: Erectile dysfunction (ED) has been linked to obstructive sleep apnea (OSA). This study used computed tomography (CT) to identify cephalometric and upper airway anatomic features in patients with OSA that correlate with the presence of ED. METHODS: In this prospective study, 20 CT cephalometric and upper airway measurements, most commonly associated with OSA, were analyzed in 53 age- and BMI-matched consecutive eligible subjects. Twenty-two were diagnosed with OSA and ED (OSA+/ED+), 17 with OSA without ED (OSA+/ED-), and 14 without OSA and ED (OSA-/ED-) serving as a control group. RESULTS: Although OSA+/ED+ did not differentiate significantly in CT measurements from OSA+/ED-, they showed more alterations when compared to OSA-/ED-, which included narrower bony oropharynx, longer soft palate and uvula (PNS-P), and narrower retropalatal and retrolingual airway diameter (p < 0.05). Binary forward stepwise model analysis showed that PNS-P was the only significant variable in the predictive model for ED in patients with OSA (OR = 1.129, 95 % CI = 1.0005-1.268, p = 0.041). In the OSA+/ED+ group, PNS-P correlated with the percentage of total sleep time with oxygen saturation <90 % (r = 0.61, p < 0.01) and was the only determinant in the relevant predictive model (n = 22, model R = 0.612, adjusted R (2) = 0.337, F = 10.167, p < 0.005). CONCLUSIONS: Characteristics of the craniofacial and upper airway structures suggest that a longer soft palate and uvula may be important risk factors for the concurrence of ED in patients with OSA. Only OSA+/ED+ showed significant narrowing in the retropalatal, retrolingual, and bony oropharynx level when compared with BMI-matched OSA-/ED-.

Experience and limited lighting may affect sleepiness of tunnel workers.

BACKGROUND: Working on shifts, especially on a night shift, influences the endogenous sleep regulation system leading to diminished sleep time and increased somnolence. We attempted to evaluate the impact of shifts on sleepiness and correlate the sleepiness score to the experience in a shift schedule. MATERIALS AND METHODS: This cross-sectional study consists of 42 male and 2 female workers involved in a tunnel construction. They underwent spirometry, pulse oximetry and were asked to complete the Epworth Sleepiness Scale questionnaire. RESULTS: Statistical analysis revealed that workers of lower Epworth had a mean age of 43.6 years, compared to the mean age of 36.4 years of workers with higher Epworth. Furthermore, workers of lower Epworth were characterized by a mean number of shift years equal to 14.8, while those of higher Epworth possessed a mean number of shift years equal to 8. The shift schedule did not reveal any statistically significant correlation. CONCLUSIONS: Workers employed for a longer time had diminished sleepiness. However, there is no relationship between night shifts and sleepiness, possibly because of exposure to artificial lighting in the construction site.

Risk factors for early mortality in haematological malignancy patients with pulmonary mucormycosis.

Pulmonary mucormycosis (PM) is a life-threatening opportunistic mycosis with a variable clinical evolution and few prognostic markers for outcome assessment. Several clinical risk factors for poor outcome present at the diagnosis of PM were analyzed in 75 consecutive hematology patients from 2000-2012. Significant variables (P < 0.1) were entered into a multivariate Cox-proportional hazard regression model adjusting for baseline APACHE II to identify independent risk factors for mortality within 28 days. Twenty-eight of 75 patients died within 4-week follow up. A lymphocyte count < 100/mm³ at the time of diagnosis (adjusted hazard ratio 4.0, 1.7-9.4, P = 0.01) and high level of lactate dehydrogenase (AHR 3.7, 1.3-10.2, P = 0.015) were independent predictors along with APACHE II score for 28-day mortality. A weighted risk score based on these 3 baseline variables accurately identified non-surviving patients at 28 days (area under the receiver-operator curve of 0.87, 0.77-0.93, P < 0.001). A risk score > 22 was associated with 8-fold high rates of mortality (P < 0.0001) within 28 days of diagnosis and median survival of 7 days versus ≥28 days in patients with risk scores ≤22. We found that APACHE II score, severe lymphocytopenia and high LDH levels at the time of PM diagnosis were independent markers for rapid disease progression and death.

Molecular testing and personalized treatment of lung cancer.

Lung malignancy is a leading cause of cancer related morbidity and mortality worldwide. The majority (85%) of cases are histologically proven non-small cell lung carcinomas (NSCLC). More than 55% of lung carcinomas harbor at least one genetic alteration, most of them being histologic subtype specific. This review summarizes the progress in personalized care of lung cancer by reviewing the literature on EGFR, ALK and KRAS molecular alterations, currently used in clinical practice, to direct the decision making process for lung cancer therapy. In addition, we will discuss some recently characterized molecular alterations whose targeting is being tested in clinical trials and holds promise for future therapeutic targeting. The role of minimally invasive procedures in lung cancer diagnosis and staging is also discussed as these techniques now play a central role in lung cancer management by providing the bulk of material for modern molecular diagnostics.

Performance of a standardized bronchoalveolar lavage protocol in a comprehensive cancer center: a prospective 2-year study.

BACKGROUND: Flexible bronchoscopy with bronchoalveolar lavage (BAL) is performed widely for the diagnosis of pulmonary infections in patients with cancer, but there is no consensus regarding the technical parameters of the lavage procedure in this setting. METHODS: The authors evaluated the mechanics (instilled and recovered volumes), diagnostic yield, and safety of a standardized BAL protocol in 284 patients with cancer who underwent bronchoscopy for the evaluation of new radiologic infiltrates. RESULTS: Physician adherence to the BAL protocol was > 90%. The most common protocol deviations were reductions in the saline volume instilled because of actual or anticipated oxyhemoglobin desaturation during the procedure. The mean volume instilled was 121.5 ± 13.9 mL, the mean volume recovered was 68.7 ± 18.1 mL, and the mean ratio of volume instilled to that recovered was 56.7% ± 14.5%. The overall diagnostic yield of BAL was 33.8% and was higher in the nonhematologic malignancy group (42.3% vs 29.4%; P = .021). The diagnostic yield in neutropenic patients was significantly higher than in non-neutropenic patients (41.5% vs 24.6%; P = .019). No major complications were encountered. CONCLUSIONS: In summary, the diagnostic performance of a standardized BAL protocol was comparable to that of nonprotocolized BAL reported in the literature with few complications. Adherence to a standardized BAL protocol may improve clinical and laboratory comparisons between studies, potentially facilitating research into the diagnosis and management of pneumonia in patients with cancer.

Positive association between two polymorphic sites (+134 insA/delA and G198T) of the endothelin-1 gene and chronic obstructive pulmonary disease. A case-control study.

Endothelin-1 (ET-1) has been implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) for establishing an inflammatory loop in the respiratory mucosa that could become independent from the initial irritant factor. Common causes of COPD exacerbations are associated with elevated ET-1 sputum concentrations. Genetic variants of the ET-1 gene, that lead to elevated ET-1 peptide levels, have not been investigated in COPD. We performed a case control, genetic study to assess possible associations of two polymorphisms of the ET-1 gene, an adenine insertion (+134 insA/delA) and a guanine to thymine transversion (G198T) with the COPD phenotype and disease severity. The genotypes of 209 subjects, 107 COPD smokers (patients) and 102 non-COPD smokers (controls) were examined. Statistical analysis revealed that the 3A/4A and 4A/4A genotypes were more common (P<0.01) in patients. Moreover, a protective effect against COPD of the TT genotype (G198T) was exhibited. COPD smokers were carrying more frequently the GG genotype and less frequently the TT genotype (P=0.047). Diplotypic analysis revealed that subjects carrying the 3A3A;TT genotype had a lower risk of COPD development (P=0.027). Within the COPD patient group carriers of the GT genotype had more often mild or moderate COPD compared to patients carrying the GG genotype (P=0.004). Haplotypic distribution revealed that carriers of the 4A:T and 4A:G haplotypes were in increased risk of COPD development. Additionally, patients with the 3A:G haplotype were in increased risk of developing severe COPD, whereas patients with the 3A:T and 4A:T had most probably mild-moderate COPD.

Targeting leukotrienes for the treatment of COPD?

New drugs and new approaches of the treatment of chronic obstructive pulmonary disease (COPD) are needed. Despite recent advances in medical therapeutics, treatment of patients with COPD remains largely symptomatic. Although inhaled corticosteroids are currently the drug of choice for anti-inflammatory therapy, the inflammatory process in COPD is essentially steroid resistant. By now, COPD has been increasingly recognized as an inflammatory disease characterized by sputum neutrophilia and, in some cases, eosinophilia. Moreover other cell types thought to play the predominant role in COPD, are cytotoxic T lymphocytes (CD8+ T) cells and macrophages. Leukotriene B4, (LTB 4), a neutrophil and T cell chemoattractant which is produced by macrophages, neurophils and epithelial cells, is a potent inflammatory mediator. Also cysteinyl leukotrienes (LTC4, LTD4 and LTE4) are known to induce mucus secretion, inflammatory cell infiltration, increase vascular permeability and tissue edema, damage ciliary clirens, and cause severe bronchoconstriction. These are derivatives of arachidonic acid, metabolized via 5-lypoxygenase (5-LO) pathway. There are several sites along this pathway that antileukotriene agents exert their action and at the end-organ receptors. They are classified into two major categories: receptor antagonists and synthesis inhibitors. Beneficial effects on therapy of patients with COPD have already derived from studies, while they seem well tolerated. More studies are underway.

Pulmonary arterial hypertension: need to treat.

Pulmonary Arterial Hypertension (PAH) is defined by a persistent elevation in pulmonary artery pressure with normal left-sided pressures. It is characterized by increased pulmonary vascular resistance due to increased vascular tone and structural remodeling of pulmonary vessels. PAH is a quite rare condition, thus considering the rarity, subtle presentation, and diagnostic dilemma commonly posed by this disease, underdiagnosis and underreporting are probably widespread. In order to reach a diagnosis the use of echocardiography, right-heart catheterization and the six-minute walk test is essential. As far as therapy is concerned, the patient should be supported by oxygen, diuretics, anticoagulants, digoxin and suggest life-style changes. After diagnosing the condition ca-blockers should be administered to those who respond positively in acute vasodilation test. Other agents used, target the endothelin pathway (ET-1 blockers such as bosentan), the NO pathway (sildenafil, inhaled NO, L-arginine) and the prostacyclin pathway (prostacyclin analogues). In some cases surgical treatment is essential (atrial septestomy, pulmonary endarterectomy, lung and heart transplantation). Finally, future therapies include administration of VIP and SSRIs. The goals of evaluating pulmonary hypertension are detection, definition of severity and the nature of the hemodynamic lesion and its consequences, diagnosis of causal or associated conditions, and determination of optimal therapy.

The alcoholic lung disease: historical background and clinical features.

SUMMARY: The purpose of this review article is to prove the damage that alcohol causes to the respiratory system. We will make a brief review of alcohols history in the course of the centuries till nowadays. The problem of addiction to alcohol (alcoholism) will be examined for several countries. Alcohol's metabolism is another topic to be discussed parallel to its pharmacological action. In addition, alcohol's impact on the respiratory system varies from damaging the mucociliary system to the regulation of breathing and from the sleep apnea syndrome to diffusion disorders. "Alcoholic lung disease" constitutes a syndrome despite the fact that the damage of the lung due to concurrent smoking and drug use is often indistinguishable.

Role and pharmacogenomics of TNF-alpha in asthma.

Asthma is a chronic heterogeneous inflammatory disease of the respiratory system in which numerous cytokines play a significant role. Among them TNF-alpha (tumour necrosis factor alpha), a proinflammatory cytokine, has a predominant role in orchestrating airway inflammation and affecting treatment outcome. In this review we attempt to summarize the involvement of TNF-alpha in the pathogenesis of asthma, illustrate variations of TNF-alpha gene that potentially influence asthma phenotype and highlight promising therapies by blocking the production of TNF-alpha or inhibiting its action. A cytokine specific target therapy seems to be very promising since agents that block TNF-alpha slow disease progression, suppress inflammation and in some cases induce remission of chronic inflammation.

Pulmonary alveolar microlithiasis in a patient with rheumatic valvular heart disease.

Pulmonary alveolar microlithiasis is a rare disease characterized by widespread intra-alveolar calcification of both lungs that is asymptomatic in the early stages. The disease typically follows a protracted course, and death can occur in 5 to 41 years after the initial diagnosis. Rheumatic fever is a multisystemic inflammatory disease that afflicts the child and juvenile population, and it is still very common in developing countries. Valve failure is the condition most linked to increased morbidity and mortality rates in this population and is the most severe complication of rheumatic fever, with consequent onset of chronic heart valve disease. We present a case of a female patient with a potential diagnosis of pulmonary alveolar microlithiasis with concurrent rheumatic valvular disease.

Genetic alterations of glutathione S-transferases in asthma: do they modulate lung growth and response to environmental stimuli?

Glutathione S-transferases (GSTs) constitute a super family of dimeric phase II metabolic enzymes that catalyze the conjugation of reduced glutathione with various electrophilic compounds and reactive oxygen species (ROS). Failure to detoxify ROS, as a sequel of altered GST genotype is able to aggravate the inflammatory cascade, promote bronchoconstrictor mechanisms, activate asthma-like symptomatology, and hamper lung development. Intriguingly, the same GST genotype can aggravate or improve physiological traits and maturation of respiratory system, from gestation to late adulthood. This article attempts to unravel the complex interaction of GST's genetic variations with "inner" and "outer", polymorphic and erratic, human environment (tobacco smoke, urban pollution, workplaces, and in utero status). Considering that these variations are very frequent among ethnicities and that GSTs play a part in respiratory system formation and maturation, they appear to be of great interest for the clinician and the researcher in this field.

Aseptic femoral head necrosis in a patient receiving long term courses of inhaled and intranasal corticosteroids.

Aseptic (avascular) necrosis of the femoral head in adults has been associated with a variety of disease entities. It is also recognized as a potential complication of systemic corticosteroid therapy. Inhaled corticosteroids are the first line anti-inflammatory agents for the long term treatment of asthma. However, long term treatment of asthma with inhaled corticosteroids has been accompanied by concern about both systemic and topical side effects. The most worrying potential systemic effects are adrenal insufficiency, growth suppression, glaucoma and osteoporosis. Fluticasone proprionate may be prescribed at higher doses to relieve respiratory symptoms in the belief that it generates fewer side effects than other inhaled steroids. Studies have shown that fluticasone is safer than beclomethasone or budesonide, with limited oral absorption and extensive hepatic first pass metabolism leading to a lower systemic bioavailability. However growth retardation and asymptomatic adrenal suppression in children receiving high-dose fluticasone have been reported. We report a rare case of avascular osteonecrosis of the femoral head associated with the use of long term inhaled fluticasone propionate along with the intranasal application of triamcinolone acetonide.

DNA sequence variations of metalloproteinases: their role in asthma and COPD.

Asthma and chronic obstructive pulmonary disease (COPD) are complex genetic diseases that cause considerable morbidity and mortality worldwide. Genetic variability interacting with environmental and ethnic factors is presumed to cause tobacco smoke susceptibility and to influence asthma severity. A disintegrin and metalloproteinase 33 (ADAM33) and matrix metalloproteinase-9 (MMP9) appear to have important roles in asthma and COPD pathogenesis. ADAM33 and MMP9 genetic alterations could possibly contribute to the establishment and progression of these multifactorial diseases, although their association with the clinical phenotypes has not yet been elucidated. However, the occurrence of these alterations does not always result in clear disease, implying that either they are an epiphenomenon or they are in proximity to the true causative alteration. This review summarises the most recent literature dealing with the genetic variations of metalloproteinases and outlines their potential pathogenetic outcome.

Genetics of chronic obstructive pulmonary disease, beyond a1-antitrypsin deficiency.

It is known that only 10-20% of smokers develop COPD, implying that apart from environmental features, additional factors such as genetic variability contribute to smoke susceptibility. This proposal is in compatibility with the "Dutch Hypothesis", formulated in the early 60's. Alpha-1-antitrypsin gene was implicated in the pathogenesis of COPD, especially the homozygous state of z allele. Since then many other genes have stepped forward as possible contributors to COPD development. In the present review we attempt to summarize the majority of these, including the genes of matrix metalloproteinases and their inhibitors, elastin, serpine2, tumor necrosis factor - a, transforming growth factor beta, a variety of interleukins and their receptors and antagonists, high affinity IgE receptor , human calcium-activated chloride channel 1, heme oxygenase, vascular endothelial growth factor, microsomal epoxide hydrolase, glutathione S-transferase, cytochrome P45O, superoxide dismutase, vitamin D binding protein, beta2-adrenergic receptor, Toll like receptor, human B defensins, mucins, cystic fibrosis transmembrane regulator, surfactant protein and Nuclear Factor E2 Related Factor 2.