Fotis Sampsonas

Pulmonary complications in diabetes mellitus

Clear decrements in lung function have been reported in patients with diabetes over the past two decades, and many reports have suggested plausible pathophysiological mechanisms. However, there are no reports of functional limitations of activities of daily living ascribable to pulmonary disease in patients with diabetes. This review attempts to summarize the available information from the present literature, to describe the nature of the lung dysfunction in diabetes and the emerging clinical implications of such dysfunction.

The Role of Endothelin-1 in Obstructive Sleep Apnea Syndrome and Pulmonary Arterial Hypertension: Pathogenesis and Endothelin-1 Antagonists

Obstructive Sleep Apnea Syndrome (OSAS) is a recognized risk factor for cardiovascular disorders and in some cases is complicated with Pulmonary Arterial Hypertension (PAH), as the endothelium is affected. Recent studies provide strong evidence for endothelial dysfunction in obstructive sleep apnea. The resultant vasoconstriction, abnormal cell proliferation and hyper-coagulability may lead to the initiation or progression of atherosclerotic cardiovascular and cerebrovascular disorders, which are frequently encountered in OSA patients. While the currently available therapies for OSAS, such as Continuous Positive Airway Pressure therapy (CPAP therapy), improve endothelial dysfunction, they are not well-tolerated by patients. CPAP therapy can reduce nocturnal hypoxemias and decrease noradrenaline circulating levels, but does not affect ET-1 plasma levels. Potent and selective Endothelin-1 receptor antagonists have been developed and have shown promising results in the treatment of cardiovascular diseases such as pulmonary arterial hypertension, acute and chronic heart failure, hypertension, renal failure, and atherosclerosis. However, results are often contrasting and complicated because of the tissue-specific vasoconstrictor actions of Endothelin-B receptors and the fact that endothelin is an autocrine and paracrine factor whose activity is difficult to measure in vivo.

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.

Role and Pharmacogenomics of TNF-α in Asthma

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

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.

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.

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.

Neuromuscular Alterations of Upper Airway Muscles in Patients with OSAS: Radiological and Histopathological Findings

This article reviews studies of upper airway muscles in humans, observed in patients with obstructive sleep apnea syndrome (OSAS). These studies include neuromuscular abnormalities of the upper airway muscles, along with changes of the upper airway lumen which is narrower in patients with OSAS than normal subjects. Several approaches have been made in the imaging of the upper airway using X-ray, CT, and MRI in order to characterize the severity of OSAS. Up to date results on histopathology of the muscles across with nervous lesions, are also reviewed.