Phenotypic, functional, and metabolic heterogeneity of immune cells infiltrating non–small cell lung cancer.

Lung cancer is the leading cancer in the world, accounting for 1.2 million of new cases annually, being responsible for 17.8% of all cancer deaths. In particular, non–small cell lung cancer (NSCLC) is involved in approximately 85% of all lung cancers with a high lethality probably due to the asymptomatic evolution, leading patients to be diagnosed when the tumor has already spread to other organs. Despite the introduction of new therapies, which have improved the long-term survival of these patients, this disease is still not well cured and under controlled. Over the past two decades, single-cell technologies allowed to deeply profile both the phenotypic and metabolic aspects of the immune cells infiltrating the TME, thus fostering the identification of predictive biomarkers of prognosis and supporting the development of new therapeutic strategies. In this review, we discuss phenotypic and functional characteristics of the main subsets of tumorinfiltrating lymphocytes (TILs) and tumor-infiltrating myeloid cells (TIMs) that contribute to promote or suppress NSCLC development and progression. We also address two emerging aspects of TIL and TIM biology, i.e., their metabolism, which affects their effector functions, proliferation, and differentiation, and their capacity to interact with cancer stem cells

Molecular mechanisms and cellular contribution from lung fibrosis to lung cancer development.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial lung 28 disease (ILD) of unknown etiology, with a median survival of 2-4 years from the time of diagnosis. 29 Although IPF has unknown etiology by definition, there have been identified several risks factors 30 increasing the probability of the onset and progression of the disease in IPF patients such as cigarette 31 smoking and environmental risks factors associated to domestic and occupational exposure. Among 32 them, cigarette smoking together with concomitant emphysema might predispose IPF patients to 33 lung cancer (LC), mostly to non-small cell lung cancer (NSCLC), increasing the risk of lung cancer 34 development. To this purpose, IPF and LC share several cellular and molecular processes driving 35 the progression of both pathologies such as fibroblast transition proliferation and activation, endo- 36 plasmic reticulum stress, oxidative stress, and many genetic and epigenetic markers that predispose 37 the IPF patients to LC development. Nintedanib, a tyrosine-kinase inhibitor, was firstly developed 38 as an anticancer drug and then recognized as an anti-fibrotic agent based on the common target 39 molecular pathway. In this review our aim is to describe the updated studies on common cellular 40 and molecular mechanisms between IPF and lung cancer, whose knowledge might help to find 41 novel therapeutic targets for this disease combination

Dissecting the Role of Mesenchymal Stem Cells in Idiopathic Pulmonary Fibrosis:Cause or Solution

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonias, characterized by chronic and progressive fibrosis subverting the lung’s architecture, pulmonary functional decline, progressive respiratory failure, and high mortality (median survival 3 years after diagnosis). Among the mechanisms associated with disease onset and progression, it has been hypothesized that IPF lungs might be affected either by a regenerative deficit of the alveolar epithelium or by a dysregulation of repair mechanisms in response to alveolar and vascular damage. This latter might be related to the progressive dysfunction and exhaustion of the resident stem cells together with a process of cellular and tissue senescence. The role of endogenous mesenchymal stromal/stem cells (MSCs) resident in the lung in the homeostasis of these mechanisms is still a matter of debate. Although endogenous MSCs may play a critical role in lung repair, they are also involved in cellular senescence and tissue ageing processes with loss of lung regenerative potential. In addition, MSCs have immunomodulatory properties and can secrete anti-fibrotic factors. Thus, MSCs obtained from other sources administered systemically or directly into the lung have been investigated for lung epithelial repair and have been explored as a potential therapy for the treatment of lung diseases including IPF. Given these multiple potential roles of MSCs, this review aims both at elucidating the role of resident lung MSCs in IPF pathogenesis and the role of administered MSCs from other sources for potential IPF therapies

Physiological effects of lung protective ventilation in patients with lung fibrosis and usual interstitial pneumonia pattern versus primary ARDS: a matched-control study.

Background- Although patients with interstitial pneumonia pattern (ILD-UIP) and acute exacerbation (AE) leading to severe acute respiratory failure may require invasive mechanical ventilation (MV), physiological data on lung mechanics during MV are lacking. We aimed at describing the physiological effect of lung protective ventilation in patients with AE-ILD-UIP compared with primary ARDS. Methods- Partitioned lung and chest wall mechanics were assessed in a series of AE-ILD-UIP patients matched 1:1 with primary ARDS as controls (based on BMI and PaO2/FiO2 ratio). Three PEEP levels (zero=ZEEP, 4-8 cmH2O=PEEPLOW, and titrated to achieve positive end-expiratory transpulmonary pressure-PL,EE=PEEPTITRATED) were used for measurements. Results- Ten AE-ILD-UIP patients and 10 matched ARDS were included. In AE-ILD-UIP median PL,EE at ZEEP was - 4.3 [-7.6 – -2.3] cmH2O and lung elastance (EL) 44 [40 – 51] cmH2O/L. At PEEPLOW, PL,EE remained negative and EL did not change (p=0.995) versus ZEEP. At PEEPTITRATED, PL,EE increased to 0.8 [0.3 – 1.5] cmH2O and EL to 49 [43 – 59] (p=0.004 and p<0.001 compared to ZEEP and PEEPLOW, respectively). PL decreased at PEEPLOW (p=0.018) and increased at PEEPTITRATED (p=0.003). In matched ARDS control PEEP titration to obtain a positive PL,EE did not result in significant changes in EL and PL. Conclusions- In mechanically ventilated AE-ILD-UIP patients, differently than in patients with primary ARDS, PEEP titrated to obtain a positive PL,EE significantly worsened lung mechanics

Molecular mechanisms and physiological changes behind benign tracheal and subglottic stenosis in adults.

Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different etiology. Although iatrogenic etiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent etiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS

Fibrotic Idiopathic Interstitial Lung Disease: The Molecular and Cellular Key Players

Interstitial lung diseases (ILDs) that are known as diffuse parenchymal lung diseases (DPLDs) lead to the damage of alveolar epithelium and lung parenchyma, culminating in inflammation and widespread fibrosis. ILDs that account for more than 200 different pathologies can be divided into two groups: ILDs that have a known cause and those where the cause is unknown, classified as idiopathic interstitial pneumonia (IIP). IIPs include idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) known also as bronchiolitis obliterans organizing pneumonia (BOOP), acute interstitial pneumonia (AIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), and lymphocytic interstitial pneumonia (LIP). In this review, our aim is to describe the pathogenic mechanisms that lead to the onset and progression of the different IIPs, starting from IPF as the most studied, in order to find both the common and standalone molecular and cellular key players among them. Finally, a deeper molecular and cellular characterization of different interstitial lung diseases without a known cause would contribute to giving a more accurate diagnosis to the patients, which would translate to a more effective treatment decision

Raw mass spectrometry data_Samarelli and Tonelli

Raw data for mass spectrometry analysis from patient</p

Environmental Causes of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF), the most common and severe of the idiopathic interstitial pneumonias, is a chronic and relentlessly progressive disease, which occurs mostly in middle-aged and elderly males. Although IPF is by definition “idiopathic”, multiple factors have been reported to increase disease risk, aging being the most prominent one. Several occupational and environmental exposures, including metal dust, wood dust and air pollution, as well as various lifestyle variables, including smoking and diet, have also been associated with an increased risk of IPF, probably through interaction with genetic factors. Many of the predisposing factors appear to act also as trigger for acute exacerbations of the disease, which herald a poor prognosis. The more recent literature on inhalation injuries has focused on the first responders in the World Trade Center attacks and military exposure. In this review, we present an overview of the environmental and occupational causes of IPF and its pathogenesis. While our list is not comprehensive, we have selected specific exposures to highlight based on their overall disease burden