The milky way

Mediastinal masses may present with signs and symptoms due to either compression of mediastinal structures or systemic effects of the underlying disease. The present case highlights the advantages of interventional pulmonology in the diagnosis of lymphoma as a cause of chylothorax and superior vena cava syndrome

Dual polarization of human alveolar macrophages progressively increases with smoking and COPD severity

BACKGROUND: It is known that tissue macrophages derive not only from blood monocytes but also from yolk sac or fetal liver, and the tissue of residence guides their function. When isolated, they lose tissue specific signatures, hence studies of human macrophages should be ideally done directly in the tissue. The aim of this study was to investigate directly in human lung tissue the polarization of alveolar macrophage (AM), classic (M1) or alternative (M2), in health and disease, using COPD as a model. METHODS: Surgical lungs from 53 subjects were studied: 36 smokers whose FEV(1) varied from normal to severe COPD, 11 non-smokers and 6 normal donors. iNOS and CD206 immunohistochemistry was used to quantify the percentage of AM polarized as M1 or M2 in lung sections. RESULTS AND DISCUSSION: The percentage of M1 and M2 increased progressively with smoking and COPD severity, from 26% to 84% for M1 and from 7% to 78% for M2. In donors 74% of AM were negative for M1 and 93% for M2. Confocal microscopy showed co-localization of M1 and M2 in the same AM in severe COPD. CONCLUSION: In normal lungs alveolar macrophages were mostly non-polarized. With smoking and COPD severity, M1 and M2 polarization increased significantly and so did the co-expression of M1 and M2 in the same alveolar macrophage. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12931-017-0522-0) contains supplementary material, which is available to authorized users

inflammation modifiers in the development of obstructive lung diseases

La BPCO e l’asma costituiscono le principali pneumopatie ostruttive e affliggono, complessivamente, una persona su sei. Nonostante le somiglianze nella manifestazione clinica, queste condizioni derivano da meccanismi patogenetici completamente diversi responsabili di specifiche risposte infiammatorie. La BPCO si presenta tipicamente con limitazione al flusso non completamente reversibile, causata da un anormale risposta infiammatoria nelle piccole vie aeree e nel parenchima polmonare, innescata dal fumo di sigaretta, che, nei fumatori suscettibili, persiste anche dopo la cessazione dell’abitudine tabagica. L’infiammazione cronica che coinvolge le vie aeree nell’asma, invece, è innescata dall’interazione tra fattori genetici e ambientali e si associa a iperreattività bronchiale e variabile limitazione al flusso aereo. Oggi è chiaro che l’iniziale risposta infiammatoria innata innescata dal fumo, se non controllata, promuove una risposta immune acquisita responsabile dello sviluppo di BPCO. In alcuni fumatori questa risposta infiammatoria acquisita può evolvere in una reazione autoimmune che distrugge il polmone comportando forme gravi di BPCO. La persistente attivazione immunologica dovuta alla disregolazione della risposta immunitaria appare quindi cruciale nello sviluppo e nella progressione della BPCO. In modo simile, alla base dello sviluppo dell’asma vi è un’aberrante reazione immunitaria a stimoli ambientali (virus, allergeni e inquinamento). L’asma è considerata una patologia eterogenea sostenuta da molteplici patwhays biologici che si manifestano con sintomi simili alla BPCO (dispnea, respiro sibilante e tosse). In breve, gli “endotipi” di asma (ovvero sottotipi di malattia con distinti meccanismi molecolari e patogenetici) si possono classificare come di “tipo 2” e “non di tipo 2” a seconda del livello di infiammazione T helper 2, caratterizzata da eosinofili, mastociti, basofili e linfociti B secernenti IgE. Tali meccanismi puntano al ruolo centrale della risposta infiammatoria al fumo nella BPCO e agli stimoli ambientali e intrinseci nell’asma. Lo scopo del mio progetto di dottorato è stato quello di indagare il ruolo dei modulatori dell’infiammazione nello sviluppo delle pneumopatie ostruttive e nell’evasione da queste stesse, nel tentativo di chiarire il ruolo del sistema immunitario nella patogenesi e negli outcomes clinici di queste malattie. Nella BPCO ci siamo focalizzati sul ruolo patogenetico di due tipi di cellule immunitarie: i linfociti e gli eosinofili. In uno studio longitudinale prospettico durato 5 anni abbiamo analizzato il numero dei linfociti e degli eosinofili circolanti, misurati annualmente, in un gruppo di fumatori con e senza BPCO. Abbiamo osservato che bassi livelli di linfociti e un loro rapido declino sono fattori di rischio indipendenti di mortalità. I livelli di eosinofili, invece, non sono risultati associati alla frequenza delle riacutizzazioni nella popolazione studiata mentre l’eosinofilia periferica è risultata associata ad una maggiore sopravvivenza. Analizzando l’interazione tra cellule infiammatorie, abbiamo intrapreso lo studio delle EV, submicroscopici veicoli di messaggi intercellulari. Abbiamo perfezionato un metodo per identificare le EV nel BAL e abbiamo osservato che la maggior parte delle EV nel BAL originavano dai macrofagi alveolari e che il loro numero era maggiore nei soggetti affetti da BPCO. Ci siamo dunque concentrati sul contenuto delle EV osservando che erano cariche di SOCS3, una proteina immuno-modulatrice, e che i miRNAs regolatori di SOCS3 erano alterati nella BPCO. Per lo studio della patogenesi dell'asma abbiamo collaborato con l'Università di Oxford. Tecniche di metagenomica sono state applicate per caratterizzare il microbioma delle vie aeree nell'asma e identificare tratti curabili di asma "non T2".COPD and asthma are the main obstructive lung diseases, globally affecting 1/6 people worldwide. In spite of similar clinical manifestations, these conditions result from completely different pathogenic mechanisms responsible for peculiar inflammatory responses. COPD patients typically present a limitation of airflow which is not fully reversible and is caused by an abnormal inflammatory response in the small airways and lung parenchyma, driven by an exaggerate reaction to cigarette smoke that, in susceptible smokers, persists even after smoking cessation. The chronic inflammation that involves airways in asthma, instead, is driven by the interaction between heritable factors and environmental exposure and is associated to airway hyper-responsiveness and variable airflow obstruction. It is now evident that the initial innate inflammation elicited by smoking, unless controlled and minimized, triggers an adaptive immune response associated to the development of COPD. In some smokers, this uncontrolled adaptive immune inflammation could evolve into an autoimmune reaction that destroys the lung, causing severe COPD. Therefore, a persistent immune activation due to a deregulation of the immune response appears to be crucial for both the development and the progression of COPD. Similar to COPD, an aberrant immune reaction to environmental triggers (virus, allergens and pollution) underlies the development of asthma. Indeed, asthma is now recognized as a heterogeneous disease sustained by multiple biologic pathways that eventually manifest with similar symptoms (shortness of breath, wheezing and cough). Shortly, asthma “endotypes” (i.e. subsets of disease with a distinct molecular mechanism and pathogenesis) can be distinguished into type-2 “high” and type-2 low subgroups, according to the degree of T helper 2 inflammation (characterized by eosinophils, mast cells, basophils, and IgE-producing B-cells). All these mechanisms point to a central role of the inflammatory response to smoking in COPD and to environmental and intrinsic triggers in asthma. The aim of my PhD project was to investigate the role of inflammation modifiers in the development of obstructive lung diseases, or evasion from them, in an attempt to clarify the role of immune system in the pathogenesis and clinical outcomes of these diseases. In COPD we first focused on the role of 2 immune cells: lymphocytes and eosinophils. By the analysis of circulating lymphocyte and eosinophil count prospectively collected in a 5 year longitudinal study on smokers with and without COPD, we found that low blood lymphocytes (BL) and BL decline were independent risk factors for mortality. Eosinophil levels, instead, did not predict exacerbation rate in our population and, more interestingly, high eosinophil numbers were associated to higher survival. These findings were confirmed in a population of severe exacerbators admitted to our ward. A relevant percentage of these patients had concomitant acute heart failure, suggesting how complex might be the diagnosis of “COPD exacerbation”. Investigating the interaction between inflammatory cells, we approached the study of EVs, tiny shuttles of cell-cell communications. We developed a method to detect and characterized BAL EVs, and found that the majority of them derived from alveolar macrophages and that their number significantly increased in COPD. Focusing on EV content in COPD, we described fir the first time that alveolar macrophage-derived EVs in BAL were enriched in SOCS3, a crucial immune modulator whose expression is similarly enhanced in COPD alveoli, as observed by our pathological study. Finally, we assessed the miRNA content in BAL EV, finding that SOCS3 post transcriptional regulators, miR-19a-3p and miR-221-3p were reduced in COPD. Studying asthma pathogenesis, we focused on the mechanisms of T-2 low diseaese and applyed metagenomic techniques to study airway microbiome

The milky way

Mediastinal masses may present with signs and symptoms due to either compression of mediastinal structures or systemic effects of the underling disease. The present case highlights the advantages of interventional pulmonology in the diagnosis of lymphoma as a cause of chylothorax and superior vena cava syndrome

On the delayed approach to mediastinal lymphomas in the SARS-CoV2 era

COVID-19 outbreak dramatically affected the health system, not only by direct infection but also depleting health resources and limiting patients' access to medical advice. We presented the cases of four patients admitted to the Respiratory Department for mediastinal masses who, even complaining mass-related symptoms, delayed hospital admission being afraid of SARS-Cov2 infection. The final diagnosis of primary mediastinal large B-cell lymphoma was achieved by interventional pulmonology procedures including bronchoscopy, ultrasound and CT-guided biopsies. These semi-invasive techniques may speed up the diagnostic workout and, sometimes, spare thoracic surgery. The prognosis of this kind of non-Hodgkin lymphomas depends on an early and aggressive therapeutic approach. Considering that, the delayed healthcare utilization due to patients' concern to seek for medical advice in COVI D-19 era should not be underestimated

The yellow brick road

Yellow nail syndrome is an uncommon condition characterized by dystrophic yellow nails, lymphedema and respiratory tract involvement. This syndrome typically shows up in middle-aged patients. Although several etiologies have been described, to date, the exact underlying mechanism remains unclear. The most supported pathogenetic hypothesis argues that it results from an abnormal lymphatic drainage. Hereby, we describe the associations of yellow nail syndrome typical features in a 73-year-old man with an acute onset of symptoms. He was admitted to our hospital with acute respiratory failure requiring non-invasive ventilation. Despite our advice, he rapidly relapsed. Taking care of his multiple comorbidities - cardiomyopathy, sleep apnea syndrome and severe obstructive deficit - his symptoms finally improved. Adherence to nocturnal non-invasive ventilation, bronchodilator therapy and pulmonary rehabilitation provided him stability. Acute and critical presentation could mystify the diagnosis of rare syndromes such as the yellow nail syndrome. Its precocious recognition reinforced our approach justifying a detailed screening of the patient's conditions

Quando il saggio indica la luna lo stolto guarda il dito

Presentiamo il caso di un uomo affetto da dispnea ed ipossiemia persistenti, ma con esame obiettivo, volumi polmonari e radiografia del torace nella norma. Anamnesi patologica remota sostanzialmente muta. Questa presentazione deve far pensare all’ipertensione polmonare idiopatica, una patologia relativamente rara che deve essere sospettata nei pazienti che lamentano dispnea da sforzo, ipossiemia, dolore toracico oppressivo o tosse persistente, in presenza di un quadro funzionale e radiologico essenzialmente negativo

Alpha-1 antitrypsin deficiency: Beyond the protease/antiprotease paradigm

From the discovery that alpha-1 antitrypsin (AAT) was an effective inhibitor of neutrophil elastase originated the classic paradigm of protease/antiprotease imbalance, linking lung destruction to the unopposed effect of proteases in patients with the deficiency. Notwithstanding its importance as an antiprotease, it has become evident that alpha-1 antitrypsin has important antiinflammatory and immune-regulatory activities, which may be critically involved in lung destruction. We review here recent evidence showing that, indeed, an important adaptive immune reaction is present in lungs with AAT deficiency, similar to the one seen in severe chronic obstructive pulmonary disease with normal AAT. On the basis of recent evidence from epidemiological, clinical, and pathogenetic studies, it is likely time to move on from the original protease/antiprotease hypothesis for the production of emphysema toward a more complex paradigm, involving the antiinflammatory and immune modulating functions of AAT

Morphologic-Molecular Transformation of Oncogene Addicted Non-Small Cell Lung Cancer

Patients with non-small cell lung cancer, especially adenocarcinomas, harbour at least one oncogenic driver mutation that can potentially be a target for therapy. Treatments of these oncogene-addicted tumours, such as the use of tyrosine kinase inhibitors (TKIs) of mutated epidermal growth factor receptor, have dramatically improved the outcome of patients. However, some patients may acquire resistance to treatment early on after starting a targeted therapy. Transformations to other histotypes-small cell lung carcinoma, large cell neuroendocrine carcinoma, squamous cell carcinoma, and sarcomatoid carcinoma-have been increasingly recognised as important mechanisms of resistance and are increasingly becoming a topic of interest for all specialists involved in the diagnosis, management, and care of these patients. This article, after examining the most used TKI agents and their main biological activities, discusses histological and molecular transformations with an up-to-date review of all previous cases published in the field. Liquid biopsy and future research directions are also briefly discussed to offer the reader a complete and up-to-date overview of the topic