Pathogenesis of COPD at the cellular and molecular level.

Chronic inflammatory responses in the lung of patients with stable mild-to-severe forms of chronic obstructive pulmonary disease (COPD) play a central role in the definition, comprehension and monitoring of the disease state. A better understanding of the COPD pathogenesis cannot avoid a detailed knowledge of these inflammatory changes, altering the functional health of the lung during the disease progression. We summarize and discuss the role and principal functions of the inflammatory cells populating the large, small airways and lung parenchyma of patients with COPD of increasing severity in comparison with healthy control subjects: T and B lymphocytes, NK and innate lymphoid cells, macrophages, and neutrophils. The differential inflammatory distribution in large and small airways of patients is also discussed. Furthermore, relevant cellular mechanisms controlling the homeostasis and the "normal" balance of these inflammatory cells and of structural cells in the lung, such as autophagy, apoptosis, necroptosis and pyroptosis are as well presented and discussed in the context of the COPD severity.

New drugs under development for COPD.

The characteristic features of chronic obstructive pulmonary disease (COPD) include inflammation and remodeling of the lower airways and lung parenchyma together with activation of inflammatory and immune processes. Due to the increasing habit of cigarette smoking worldwide COPD prevalence is increasing globally. Current therapies are unable to prevent COPD progression in many patients or target many of its hallmark characteristics which may reflect the lack of adequate biomarkers to detect the heterogeneous clinical and molecular nature of COPD. In this chapter we review recent molecular data that may indicate novel pathways that underpin COPD subphenotypes and indicate potential improvements in the classes of drugs currently used to treat COPD. We also highlight the evidence for new drugs or approaches to treat COPD identified using molecular and other approaches including kinase inhibitors, cytokine- and chemokine-directed biologicals and small molecules, anti-oxidants and redox signaling pathway inhibitors, inhaled anti-infectious agents and senolytics. It is important to consider the phenotypes/molecular endotypes of COPD patients together with specific outcome measures to target new therapies to particular COPD subtypes. This will require greater understanding of COPD molecular pathologies and a focus on biomarkers of predicting disease subsets and responder/non-responder populations.

Corticosteroid resistance in asthma: Cellular and molecular mechanisms.

Inhaled glucocorticoids (GCs) are drugs widely used as treatment for asthma patients. They prevent the recruitment and activation of lung immune and inflammatory cells and, moreover, have profound effects on airway structural cells to reverse the effects of disease on airway inflammation. GCs bind to a specific receptor, the glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily and modulates pro- and anti-inflammatory gene transcription through a number of distinct and complementary mechanisms. Targets genes include many pro-inflammatory mediators such as chemokines, cytokines, growth factors and their receptors. Inhaled GCs are very effective for most asthma patients with little, if any, systemic side effects depending upon the dose. However, some patients show poor asthma control even after the administration of high doses of topical or even systemic GCs. Several mechanisms relating to inflammation have been considered to be responsible for the onset of the relative GC resistance observed in these patients. In these patients, the side-effect profile of GCs prevent continued use of high doses and new drugs are needed. Targeting the defective pathways associated with GC function in these patients may also reactivate GC responsiveness.

[Risk of diabetes mellitus during regular long-term inhaled glucocorticoid treatment in COPD patients: narrative review of the literature.] / Rischio di diabete mellito durante il trattamento regolare a lungo termine con glucocorticoidi per via inalatoria nei pazienti con BPCO: revisione narrativa della letteratura.

Glucocorticoids are anti-inflammatory drugs used in combination with inhaled bronchodilators, such as ß2-agonists and antimuscarinics, for the treatment of stable chronic obstructive pulmonary disease (COPD), to improve respiratory symptoms, such as exertional dyspnoea, and to decrease the risk of future COPD exacerbations. However, it remains controversial whether their regular long-term use increases the risk of developing diabetes mellitus. The objective of this narrative review is therefore to analyse all the randomized controlled trials performed in patients with stable COPD to identify the risk of new onset diabetes mellitus during a long-term (at least 52 weeks) regular treatment with inhaled glucocorticoids alone compared to placebo. From a literature search on PubMed, 19 studies fulfilling these criteria have been identified. The inhaled glucocorticoids administered were: fluticasone propionate (7 studies), budesonide (6 studies), mometasone furoate (3 studies), beclomethasone dipropionate (1 study), triamcinolone acetonide (1 study), and fluticasone furoate (1 study) respectively. Only 3 out of the 19 trials identified in our narrative review reported data on diabetes mellitus, and in these the incidence of diabetes mellitus was not significantly different in both treatment arms (inhaled glucocorticoids and placebo), regardless of the type of glucocorticoid used.

Role of Atypical Chemokines and Chemokine Receptors Pathways in the Pathogenesis of COPD.

Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung generally resulting from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors (such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end products (RAGE) or toll-like receptors (TLRs)) in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in preclinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes because there is redundancy in this network. However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential antiinflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of atypical chemokines in COPD pathophysiology and thereby improve COPD management.

New drugs under development for COPD.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by chronic bronchitis, emphysema, and remodeling. Its prevalence is increasing worldwide; however, there are few effective therapies, and none of the treatments currently available prevent the progression of the disease or target all of the hallmark features. The development and progression of COPD are heterogeneous, which has hampered the development of new therapies. AREAS COVERED: In this review, we cover the emergence of the improvement of existing classes of drugs including glucocorticoids, ß2-adrenoceptor agonists, phosphodiesterase inhibitors, PDE4 selective inhibitors, PDE3/PDE4 inhibitors, protease inhibitors, recombinant α1-antitrypsin and neutrophil elastase inhibitors. We also highlight new compounds that target recently identified mechanisms of COPD, new dual-action muscarinic antagonists, and ß2-agonists, kinase inhibitors, cytokine modifiers, chemokines modifiers, NF-κB inhibitors, senolytics, antioxidants, inhaled antiviral agents, anti-fibrotic compounds, and compounds stimulating lung regeneration. EXPERT OPINION: Given the myriad of potential therapeutic avenues that can be pursued, careful consideration of the phenotypes/endotypes of COPD patients will be important for personalized treatment options in the future, and a full understanding of disease mechanisms in patient subsets will ensure these emerging therapies are targeted appropriately.

A case of lung injury resembling diffuse pulmonary hemorrhage after the first administration of alemtuzumab in a patient with multiple sclerosis. Role of the HRCT.

Diffuse alveolar hemorrhage (DAH) is an acute often life-threatening condition characterized by a variable combination of hemoptysis, dyspnoea, diffuse and bilateral ground glass pulmonary opacities, anemia and hypoxemia, that can be induced by different causes, including several drugs. We report here the case of a 25-year-old woman who has been admitted to our pulmonary clinic for the onset of chest pain, cough and haemoptysis, started one week after her first treatment with alemtuzumab for multiple sclerosis. Computed tomography (CT) scan of the chest at the admission showed diffuse and bilateral ground glass pulmonary opacities. Her symptoms resolved completely without any treatment, after the interruption of alemtuzumab, and CT scan of the chest performed one month later showed total disappearance of the pulmonary opacities.

Role of the mucins in pathogenesis of COPD: implications for therapy.

Introduction: Evidence accumulated in the last decade has started to reveal the enormous complexity in the expression, interactions and functions of the large number of different mucins present in the different compartments of the human lower airways. This occurs both in normal subjects and in COPD patients in different clinical phases and stages of severity.Areas covered: We review the known physiological mechanisms that regulate mucin production in human lower airways of normal subjects, the changes in mucin synthesis/secretion in COPD patients and the clinical efficacy of drugs that modulate mucin synthesis/secretion.Expert opinion: It is evident that the old simplistic concept that mucus hypersecretion in COPD patients is associated with negative clinical outcomes is not valid and that the therapeutic potential of 'mucolytic drugs' is under-appreciated due to the complexity of the associated molecular network(s). Likewise, our current knowledge of the effects of the drugs already available on the market that target mucin synthesis/secretion/structure in the lower airways is extremely limited and often indirect and more well-controlled clinical trials are needed in this area.

Molecular links between COPD and lung cancer: new targets for drug discovery?

INTRODUCTION: COPD and lung cancer are leading causes of morbidity and mortality worldwide, and they share a common environmental risk factor in cigarette smoke exposure and a genetic predisposition represented by their incidence in only a fraction of smokers. This reflects the ability of cigarette smoke to induce an inflammatory response in the airways of susceptible smokers. Moreover, COPD could be a driving factor in lung cancer, by increasing oxidative stress and the resulting DNA damage and repression of the DNA repair mechanisms, chronic exposure to pro-inflammatory cytokines, repression of innate immunity and increased cellular proliferation. Areas covered: We have focused our review on the potential pathogenic molecular links between tobacco smoking-related COPD and lung cancer and the potential molecular targets for new drug development by understanding the common signaling pathways involved in COPD and lung cancer. Expert commentary: Research in this field is mostly limited to animal models or small clinical trials. Large clinical trials are needed but mostly combined models of COPD and lung cancer are necessary to investigate the processes caused by chronic inflammation, including genetic and epigenetic alteration, and the expression of inflammatory mediators that link COPD and lung cancer, to identify new molecular therapeutic targets.

Hereditary hyperhomocysteinemia associated with nephrotic syndrome complicated by artery thrombosis and chronic thromboembolic pulmonary hypertension: A case report.

We present here the case of a 30-year-old man with a long term history of nephrotic syndrome (NS) who developed an episode of acute left main pulmonary artery thrombosis complicated by a lung abscess. During the hospital admission was also identified a concomitant hyperhomocysteinemia. After an atypical resection of the left upper pulmonary lobe and the starting of long term anticoagulation the patient was discharged but did not attend the planned follow up visits until one year later when he was seen again for severe dyspnea and exercise intolerance. At this time chronic thromboembolic pulmonary hypertension (CTEPH) was diagnosed by lung perfusion scintigraphy and right heart catheterization. He initially refused the surgical treatment but, after six months, for the presence of worsening dyspnea was referred for bilateral pulmonary endarterectomy followed by a cardio-thoracic rehabilitation program. After a follow-up of seven years the patient is alive and in stable conditions. NS and hyperhomocysteinemia are both known risk factors for pulmonary embolism (PE), but their association with CTEPH is extremely rare. We discuss here the possible mechanisms linking these conditions. CTEPH must be suspected in any patient with NS, with or without hyperhomocysteinemia, and unexplained dyspnea.