Airway hyperresponsiveness, inflammation, and pulmonary emphysema in rodent models designed to mimic exposure to fuel oil-derived volatile organic compounds encountered during an experimental oil spill

Fuel oil-derived volatile organic compounds (VOCs) inhalation is associated with accidental marine spills. After the Prestige petroleum tanker sank off northern Spain in 2002 and the Deepwater Horizon oil rig catastrophe in 2009, subjects involved in environmental decontamination showed signs of ongoing or residual lung disease up to 5 y after the exposure. We aimed at investigating mechanisms driving persistent respiratory disease by developing an animal model of inhalational exposure to fuel oil-derived VOCs. Female Wistar and Brown Norway (BN) rats and C57BL mice were exposed to VOCs produced from fuel oil mimicking the Prestige spill. Exposed animals inhaled the VOCs 2 h daily, 5 d per week, for 3 wk. Airway responsiveness to methacholine (MCh) was assessed, and bron-choalveolar lavage (BAL) and lung tissues were analyzed after the exposure and following a 2-wk washout. Consistent with data from human studies, both strains of rats that inhaled fuel oil-derived VOCs developed airway hyperresponsiveness that persisted after the washout period, in the absence of detectable inflammation in any lung compartment. Histopathology and quantitative morphology revealed the development of peripherally distributed pulmonary emphysema, which persisted after the washout period, associated with increased alveolar septal cell apoptosis, microvascular endothelial damage of the lung parenchyma, and inhibited expression of vascular endothelial growth factor (VEGF). In this rat model, fuel oil VOCs inhalation elicited alveolar septal cell apoptosis, likely due to DNA damage. In turn, the development of a peculiar pulmonary emphysema pattern altered lung mechanics and caused persistent noninflammatory airway hyperresponsiveness. Such findings suggest to us that humans might also respond to VOCs through physiopathological pathways different from those chiefly involved in typical cigarette smoke-driven emphysema in chronic obstructive pulmonary disease (COPD). If so, this study could form the basis for a novel disease mechanism for lasting respiratory disease following inhalational exposure to catastrophic fuel oil spills

A Proposed Approach to Chronic Airway Disease (CAD) Using Therapeutic Goals and Treatable Traits: A Look to the Future

© 2020 Pérez de Llano et al.Chronic airflow obstruction affects a wide range of airway diseases, the most frequent of which are asthma, COPD, and bronchiectasis; they are clearly identifiable in their extremes, but quite frequently overlap in some of their pathophysiological and clinical characteristics. This has generated the description of new mixed or overlapping disease phenotypes with no clear biological grounds. In this special article, a group of experts provides their perspective and proposes approaching the treatment of chronic airway disease (CAD) through the identification of a series of therapeutic goals (TG) linked to treatable traits (TT) – understood as clinical, physiological, or biological characteristics that are quantifiable using biomarkers. This therapeutic approach needs validating in a clinical trial with the strategy of identification of TG and treatment according to TT for each patient independently of their prior diagnosis

The role of CD4+T cells in airway remodeling in experimental asthma /

The aim of this work was to investigate the role of CD4 + T cells, central to airway inflammation in asthma, in airway remodeling. Structural changes that occur in asthmatic airways in association with inflammation include an increase in airway smooth muscle mass, which participates in causing airway hyperresponsiveness. We aimed to gain further insights into the mechanisms that may link inflammation with remodeling using a rat model of experimental asthma. We hypothesized that CD4+ T cells drive airway smooth muscle remodeling. Adoptive transfer of CD4+ T cells from ovalbumin-sensitized rats induced increased proliferation and inhibition of apoptosis of airway myocytes in naive recipients upon repeated antigen challenge, which resulted in an increase in airway smooth muscle mass. CD4+ T cells genetically modified to express green fluorescent protein were localized by confocal microscopy in juxtaposition to airway smooth muscle cells, suggesting that CD4 + T cells may modulate smooth muscle cell function through direct cell-cell interaction in vivo. We subsequently co-cultured antigen-stimulated CD4+ T cells with cell cycle-arrested airway smooth muscle cells and demonstrated by flow cytometry that CD4+ T cells induce myocyte proliferation, dependent on T cell activation and direct T cell/myocyte contact. Reciprocally, direct cell contact prevented activation-induced T cell apoptosis as well as spontaneous apoptosis of resting T cells, suggesting T cell/myocyte cross-talk. Our data demonstrate that CD4+ T cells drive airway smooth muscle remodeling in experimental asthma, and suggest that a mechanism involving a direct "synapse" participates in CD4+ T cell regulation of myocyte turnover and induction of remodeling. The goal of genetically modifying CD4+ T cells involved technical challenges relevant to the field of gene therapy and are dealt with in detail in this thesis. Retroviral gene transduction coupled with antigenic stimulation wa

An update on the use of indacaterol in patients with COPD

Current guidelines for the management of chronic obstructive pulmonary disease (COPD) establish that bronchodilator medications are central to the symptomatic treatment of the disease. Regular treatment with long-acting bronchodilators is recommended as more effective and convenient than short-acting bronchodilators, because the long-acting agents provide greater bronchodilator efficacy and symptomatic relief, increased tolerance to exercise, and improved rate of exacerbations and quality of life test scores. Dosing regimens requiring less frequent dosing also provide improved treatment compliance. Indacaterol is a novel once-daily ultra-long-acting β 2 -agonist bronchodilator now approved in the European Union for maintenance bronchodilator treatment of airflow obstruction in adult patients with COPD, to be administered as 150 or 300 µg once-daily dose by means of a single-dose dry powder inhaler. This review focuses on providing a clinical practice-oriented synopsis of the data generated from the randomized trials during the clinical development of indacaterol, published as of the time of writing. Indacaterol has been shown to provide effective 24-h bronchodilation and a fast onset of action, with an efficacy at least comparable or superior to current bronchodilator therapy standards and with a favourable safety and tolerability profile within the β 2 -agonist drug class

Time course of airway remodelling after an acute chlorine gas exposure in mice

Abstract Accidental chlorine (Cl2) gas inhalation is a common cause of acute airway injury. However, little is known about the kinetics of airway injury and repair after Cl2 exposure. We investigated the time course of airway epithelial damage and repair in mice after a single exposure to a high concentration of Cl2 gas. Mice were exposed to 800 ppm Cl2 gas for 5 minutes and studied from 12 hrs to 10 days post-exposure. The acute injury phase after Cl2 exposure (≤ 24 hrs post-exposure) was characterized by airway epithelial cell apoptosis (increased TUNEL staining) and sloughing, elevated protein in bronchoalveolar lavage fluid, and a modest increase in airway responses to methacholine. The repair phase after Cl2 exposure was characterized by increased airway epithelial cell proliferation, measured by immunoreactive proliferating cell nuclear antigen (PCNA), with maximal proliferation occurring 5 days after Cl2 exposure. At 10 days after Cl2 exposure the airway smooth muscle mass was increased relative to controls, suggestive of airway smooth muscle hyperplasia and there was evidence of airway fibrosis. No increase in goblet cells occurred at any time point. We conclude that a single exposure of mice to Cl2 gas causes acute changes in lung function, including pulmonary responsiveness to methacholine challenge, associated with airway damage, followed by subsequent repair and airway remodelling.</p