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The article presents a study which investigated the role of pulmonary natural killer T cells (NKT) populations in IPF by analyzing bronchoalveolar lavage (BAL) fluid from patients with idiopathic pulmonary fibrosis (IPF) and healthy control subjects by quantitative polymerase chain reaction (PCR) and flow cytometry. Topics discussed include clinical characteristics of IPF, how the role of NKT cells was ascertained, and how the severity of lung lesions was graded.

Summary: Macrophage activation results in the accumulation of endogenous metabolites capable of adopting immunomodulatory roles; one such bioactive metabolite is itaconate. After macrophage stimulation, the TCA-cycle intermediate cis-aconitate is converted to itaconate (by aconitate decarboxylase-1, ACOD1) in the mitochondrial matrix. Recent studies have highlighted the potential of targeting itaconate as a therapeutic strategy for lung diseases such as asthma, idiopathic pulmonary fibrosis (IPF), and respiratory infections. This review aims to bring together evidence which highlights a role for itaconate in chronic lung diseases (such as asthma and pulmonary fibrosis) and respiratory infections (such as SARS-CoV-2, influenza and Mycobacterium tuberculosis infection). A better understanding of the role of itaconate in lung disease could pave the way for novel therapeutic interventions and improve patient outcomes in respiratory disorders. Recent studies have highlighted the potential of targeting itaconate as a therapeutic strategy for lung diseases such as asthma, idiopathic pulmonary fibrosis (IPF), and respiratory infections. This short review aims to bring together evidence which highlights a role for itaconate in chronic lung disease. A better understanding of the role of itaconate in respiratory disorders could pave the way for novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry- based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+ cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche. Idiopathic pulmonary fibrosis has been associated with aberrant expansion of KRT5-expressing basal cells. Here the authors show how changes in the ECM glycoprotein SPARC restrict the movement of KRT5+ cells, affecting their retention within fibrotic tissue. [ABSTRACT FROM AUTHOR]

The article presents the discussion on nonspecific stimuli evoking a prototypic type 2 immune response in the airways. Topics include patients with asthma correlating with Th2 inflammation and disease severity targeting the mediators in animal models ameliorating inflammation and pathology; and protease activated receptors and viral-induced necroptosis all purporting mechanisms driving the secretion of these alarmins.

Iron is an essential nutrient for numerous cellular processes. However, excess iron in the lung (e.g. inhaled in pollution/cigarette smoke) can be harmful, acting as a catalyst in the formation of free radicals. Pulmonary iron content is therefore tightly regulated and alterations in iron metabolism have been associated with chronic lung disease. In particular, patients with idiopathic pulmonary fibrosis have been reported to have numerous aspects of dysfunctional iron metabolism in the lung, including increased iron levels, presence of iron‐laden macrophages and iron‐induced oxidative stress. In a recent issue of The Journal of Pathology, Ali et al showed a mechanistic link between iron accumulation and pulmonary fibrosis pathology. Using mouse models of iron overload, the authors showed that increased iron levels resulted in reduced lung function and worse pulmonary fibrosis upon lung injury by bleomycin. Treatment with inhaled iron chelator deferoxamine ameliorated pulmonary fibrosis and prevented lung function decline in vivo. This study highlights the importance of iron homeostasis in the lung and provides evidence of pulmonary iron overload contributing to the development and progression of pulmonary fibrosis. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Macrophages are an integral part of the innate immune system and key players in pathogen clearance and tissue remodelling. Both functions are accomplished by a pivotal network of different macrophage subtypes, including proinflammatory M1 and anti-inflammatory M2 macrophages. Previously, our laboratory identified the transcription factor interferon regulatory factor 5 (IRF5) as the master regulator of the M1 macrophage polarisation. IRF5 was found to be highly expressed in human M1 compared to M2 macrophages. Furthermore, IRF5 dictates the expression of proinflammatory genes such as IL12b and IL23a whilst repressing anti-inflammatory genes like IL10. Here we show that murine bone marrow derived macrophages differentiated in vitro with GM-CSF are also characterised by high levels of IRF5 mRNA and protein and express proinflammatory cytokines upon LPS stimulation. These macrophages display characteristic expression of M1-marker MHC II but lack the M2-marker CD206. Significantly, we develop intracellular staining of IRF5- expressing macrophages and utilise it to recapitulate the in vitro results in an in vivo model of antigen-induced arthritis, emphasising their physiological relevance. Thus, we establish the species-invariant role of IRF5 in controlling the inflammatory macrophage phenotype both in vitro and in in vivo. [ABSTRACT FROM AUTHOR]

Histamine is an important allergic mediator, and studies have defined roles for both histamine 1 and 4 receptors in allergic airway inflammation. In this study, we show that histamine is necessary to generate IL-4-driven eosinophilic inflammation, as histamine-deficient mice cannot generate eosinophilic lung inflammation in response to intratracheal IL-4 and exogenous histamine restores responsiveness. This is histamine 2 receptor (H2R) dependent because H2R knockout mice fail to respond to IL-4, and a H2R agonist restores inflammation in histidine decarboxylase knockout. Furthermore, alveolar epithelial cells require H2R to produce CCL24, an eosinophil recruitment factor, whereas H2R blockade reduces CCL24 production from wild-type cells. In an allergic inflammation model, H2R knockout mice show significantly reduced eosinophilic inflammation and CCL24 expression. These data demonstrate a previously unidentified role for H2R in allergic inflammation and establishes a synergy between endogenous histamine and IL-4 that supports eosinophilic recruitment to the lung. [ABSTRACT FROM AUTHOR]

Background Anti-aging effects of high concentrations of salicylic acid (SA) peels are commonly known. Like all acids, SA can produce somatosensory and visible irritation to the skin and as such may be unsuitable for subjects with sensitive skin. Aims To provide evidence that sodium salicylate (SS) obtained from neutralization of 1% SA by sodium hydroxide can deliver significant anti-aging benefits. Methods The effects of SS were examined using three approaches: (1) evaluating its effects on stimulating the synthesis of fibrillin and collagen-1 in vivo; (2) examining its efficacy by using Fast Optical in vivo Topometry (FOITS) in a double-blind, placebo-controlled clinical study; (3) determining its effects on both expert and naïve grader assessement of wrinkles in a double-blind, placebo-controlled study. Results In the first study SS produced significant increases of the fibrillin and collagen-1 anti-aging biomarkers compared with the untreated skin control. A commercially available retinol cream delivered similar effects to SS. In the second study using FOITS we showed that the SS formulation significantly reduced wrinkle depth (Rz) and skin roughness (Ra) after 4 and 8 weeks of daily application vs. placebo (Rz: −8.2 ± 1.40% and −11.4 ± 1.07%; Ra: −7.8 ± 1.33% and −11.9 ± 0.61%; P < 0.01). In the third study reductions in wrinkle depth were observed by expert assessment at both 4 and 8 weeks for the SS-containing formulation compared to its placebo ( P < 0.05). Equally, non-expert graders recorded the SS formulation superior to its placebo. Conclusion Although the mechanism of action is not completely understood, we believe the benefits of SS are derived from its intrinsic stratum corneum exfoliation effects. All three studies demonstrate the significant anti-aging effects of SS that are especially suitable for subjects with sensitive skin. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis (PF) can be idiopathic or driven by a specific insult or disease process. Inflammation plays a role in the pathophysiology, the extent of which remains a longstanding topic of debate. More recently there has been increasing interest in a potential inciting role for aberrant lipid metabolism. Lipids are essential for the structure and function of all cell membranes but specifically in the lung for surfactant composition, intra and intercellular lipid mediators and lipofibroblasts. Clinically, there is evidence of increased lipid deposition in the subpleural space, and at a whole lung tissue level in PF. There is evidence of increased parenchymal lipid deposition and abnormal mediastinal fat shape on chest CT. A protective role for cholesterol lowering drugs including statins and ezetimibe has been described in PF. At a cellular level, fatty acid (FA), phospholipid (PL) and glucose metabolism are disordered, as is the production of lipid mediators. In this perspectives piece we put forward the argument that there is substantive clinical and biological evidence to support a role for aberrant lipid metabolism and lipid mediators in the pathogenesis of PF.