Mark G. Jones

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is a prototype of chronic, progressive, and fibrotic lung disease. Healthy tissue is replaced by altered extracellular matrix and alveolar architecture is destroyed, which leads to decreased lung compliance, disrupted gas exchange, and ultimately respiratory failure and death. In less than a decade, understanding of the pathogenesis and management of this disease has been transformed, and two disease-modifying therapies have been approved, worldwide. In this Seminar, we summarise the presentation, pathophysiology, diagnosis, and treatment options available for patients with idiopathic pulmonary fibrosis. This disease has improved understanding of the mechanisms of lung fibrosis, and offers hope that similar approaches will transform the management of patients with other progressive fibrotic lung diseases.

Antacid therapy in idiopathic pulmonary fibrosis: more questions than answers?

Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of complex cause. Gastro-oesophageal reflux (GER) and microaspiration have been proposed as risk factors for the development and progression of IPF, but robust definitive data are few. A recent international guideline conditionally recommended the use of antacid therapy (proton pump inhibitors or histamine-2-receptor antagonists) for patients with IPF, in the absence of oesophageal reflux or symptoms. In this Position Paper, we summarise the literature addressing the association between GER and IPF, and also identify future research priorities that could clarify this issue. We shed light on the process through which the guideline recommendation was achieved and aim to contextualise the recommendation for providers caring for patients with IPF.

Three-dimensional characterization of fibroblast foci in idiopathic pulmonary fibrosis

In idiopathic pulmonary fibrosis (IPF), the fibroblast focus is a key histological feature representing active fibroproliferation. On standard 2D pathologic examination, fibroblast foci are considered small, distinct lesions, although they have been proposed to form a highly interconnected reticulum as the leading edge of a “wave” of fibrosis. Here, we characterized fibroblast focus morphology and interrelationships in 3D using an integrated micro-CT and histological methodology. In 3D, fibroblast foci were morphologically complex structures, with large variations in shape and volume (range, 1.3 × 104 to 9.9 × 107 μm3). Within each tissue sample numerous multiform foci were present, ranging from a minimum of 0.9 per mm3 of lung tissue to a maximum of 11.1 per mm3 of lung tissue. Each focus was an independent structure, and no interconnections were observed. Together, our data indicate that in 3D fibroblast foci form a constellation of heterogeneous structures with large variations in shape and volume, suggesting previously unrecognized plasticity. No evidence of interconnectivity was identified, consistent with the concept that foci represent discrete sites of lung injury and repair.

A disintegrin and metalloprotease (ADAM) 33 protein in patients with pulmonary sarcoidosis

Background and objective:  A disintegrin and metalloproteinase (ADAM) 33 is a susceptibility gene associated with inflammatory lung and skin diseases. It is selectively expressed in mesenchymal cells, and its metalloprotease activity has been linked to angiogenesis and tissue remodelling. A soluble form of ADAM33 (sADAM33) has been identified in the bronchoalveolar lavage fluid (BALF) of asthmatic patients, and its levels inversely correlate with lung function. Because of its association with inflammatory lung diseases, it was hypothesized that sADAM33 is elevated in BALF of patients with pulmonary sarcoidosis.

The safety of new drug treatments for idiopathic pulmonary fibrosis.

ABSTRACT Introduction: The management of idiopathic pulmonary fibrosis (IPF) has been transformed by the recent approval of two anti-fibrotic drugs, nintedanib and pirfenidone. An increasing number of patients with IPF are receiving treatment with these novel therapies, and the risk of adverse events that may be associated with their use must be carefully evaluated. Areas covered: Safety data about nintedanib and pirfenidone is critically evaluated, including data from randomized clinical trials and post-marketing reports. Management strategies to minimize the occurrence of side effects are summarized. Expert opinion: The safety profile of the two anti-fibrotic drugs approved for clinical use in IPF patients appears to be comparable. Data from clinical trials and initial post-marketing surveillance indicate that most of the observed side effects are mild and easily manageable. However, approximately 1/5 of patients may discontinue treatment as a consequence of side effects. Careful patient counselling, and regular follow-up during therapy could reduce the rate of discontinuations. Ongoing post-marketing surveillance may further inform our understanding of the safety profile of these therapies.

Air pollution and acute exacerbations of idiopathic pulmonary fibrosis: back to miasma?

Centuries ago miasma (from μiασμα , the ancient Greek word for pollution) was considered to be a poisonous vapour filled with particles from decomposed matter. The miasmatic theory held that diseases such as cholera or the Black Death were caused by a noxious form of “bad air”, also known as “night air”, emanating from rotting organic matter [1]. In those days, breathing was considered to be a dangerous, although unavoidable, exercise. The theory was accepted from ancient times in Europe, India and China, and was eventually displaced only in the 19th century by the discovery of germs. In 1876, Robert Koch proved that a bacterium had caused anthrax and this discovery brought a definitive end to miasmatic theory. Contagionism prevailed over miasmatism and, thereafter, air was not considered a cause of human disease. Instead, the concept of “fresh air” as a beneficial factor for human health became widely accepted, until recently. After World War II, air pollution became an increasingly recognised threat, initially as a consequence of radioactive fallout from atomic warfare and testing. Subsequently, a non-nuclear event, the Great Smog of 1952 in London, which killed at least 4000 people [2], prompted some of the first major modern environmental legislation, the Clean Air Act of 1956 [3]. Following this, air pollution began to draw major public attention worldwide. Recently, the European “Year of Air” initiative has again publicised that air pollution exposure is an important threat to public health. With formal classification of outdoor air pollution as a carcinogen and evidence of associations ranging from low birth weight to acute exacerbations of chronic lung diseases such as asthma and chronic obstructive pulmonary disease (COPD), it represents an obvious candidate as a risk factor or causative agent in the pathogenesis and/or the progression of …

Pneumomediastinum leading to respiratory compromise as a complication of acute severe asthma.

A woman with asthma presented with an acute exacerbation. Initial chest X-ray (CXR) identified mild hyperinflation only. She was managed with standard therapy, but 14 hours later developed severe central chest pain. Examination revealed new facial and neck subcutaneous emphysema. She was cardiovascularly stable, and jugular venous pressure was not elevated. Repeat CXR showed subcutaneous emphysema and pneumomediastinum (Figure 1A). Chest computed tomography demonstrated large-volume pneumomediastinum, pneumopericardium, and extensive subcutaneous emphysema with air extending into the extradural spinal Figure 1. Chest X-ray sequence: (A) after onset of chest pain; (B) after mediastinotomy, demonstrating resolving pneumomediastinum. A corrugated drain inserted via a suprasternal incision remains in situ. Figure 2. Chest computed tomography scan. (A) Coronal view. (B) Axial view showing air extending into the extradural spinal canal.

The histone deacetylase inhibitor, romidepsin, as a potential treatment for pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive disease that usually affects elderly people. It has a poor prognosis and there are limited therapies. Since epigenetic alterations are associated with IPF, histone deacetylase (HDAC) inhibitors offer a novel therapeutic strategy to address the unmet medical need. This study investigated the potential of romidepsin, an FDA-approved HDAC inhibitor, as an anti-fibrotic treatment and evaluated biomarkers of target engagement that may have utility in future clinical trials. The anti-fibrotic effects of romidepsin were evaluated both in vitro and in vivo together with any harmful effect on alveolar type II cells (ATII). Bronchoalveolar lavage fluid (BALF) from IPF or control donors was analyzed for the presence of lysyl oxidase (LOX). In parallel with an increase in histone acetylation, romidepsin potently inhibited fibroblast proliferation, myofibroblast differentiation and LOX expression. ATII cell numbers and their lamellar bodies were unaffected. In vivo, romidepsin inhibited bleomycin-induced pulmonary fibrosis in association with suppression of LOX expression. LOX was significantly elevated in BALF of IPF patients compared to controls. These data show the anti-fibrotic effects of romidepsin, supporting its potential use as novel treatment for IPF with LOX as a companion biomarker for evaluation of early on-target effects.

Recent Advances and Future Needs in Interstitial Lung Diseases.

Interstitial lung diseases (ILDs) are a diverse range of conditions affecting the lung interstitium. The prototypic ILD, idiopathic pulmonary fibrosis (IPF), is a chronic progressive fibrotic lung disease with a median survival of only 3 years from the time of diagnosis. Recently significant progress has been made in both our understanding of the pathogenesis and of the therapeutic targeting of IPF. This culminated in the worldwide approval of the first antifibrotic therapies nintedanib and pirfenidone. While an important first step, patients continue to progress and better therapies are urgently required. The aim of this article is to highlight some of the recent advances that have been made in our understanding of genetics, disease classification, clinical trial design, and novel antifibrotic therapy in IPF. It discusses future priorities if we are to continue to increase the length and quality of life of patients with IPF, and considers possible approaches to translate the progress made in IPF to other progressive fibrotic lung diseases where our understanding remains limited.

Idiopathic pulmonary fibrosis: securing a confident diagnosis for every patient

Almost half a century ago Liebow and Carrington [1] proposed their landmark framework to classify the idiopathic interstitial pneumonias (IIPs), a diverse group of diffuse parenchymal lung diseases of unknown aetiology. This classification approach has since informed the principal that in IIP histopathological pattern may have clinical implications including prognosis and treatment. Five subgroups were identified, the most frequent of which was termed “usual” interstitial pneumonia (UIP) and is the pattern which, in the absence of any identifiable cause, is diagnostic of the prototypic chronic progressive fibrotic lung disease idiopathic pulmonary fibrosis (IPF) [2]. Inconsistent UIP pattern on HRCT in patients with suspected IPF should not rule out possibility of an IPF diagnosis http://ow.ly/YcVao