Adam J. Byrne

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease characterised by excessive extracellular matrix deposition, leading to respiratory failure. While the exact aetiology of IPF remains unclear, growing evidence suggests that immune dysregulation plays a pivotal role in its pathogenesis. Recent research highlights the involvement of conventional (CD4 ⁺ , CD8 ⁺ T cells as well as B cells), and unconventional T cell subsets, including natural killer T cells and mucosal-associated invariant T cells in fibrotic lung disease. Unconventional T cell subsets are known for their rapid response to stress signals, antigen-independent activation and involvement in tissue homeostasis and repair. Their potential to modulate fibrosis through interactions with fibroblasts, macrophages and epithelial cells positions them as key players in lung injury and repair mechanisms. Methods: This review explores the current knowledge of both conventional and unconventional lymphocytes in IPF, examining their contributions to fibrosis development and their potential as therapeutic targets. Conclusions: By elucidating their functions and interactions within the lung microenvironment, we provide insights into novel immunomodulatory strategies for IPF treatment.

Background: Asthma is a chronic, heterogeneous disease characterised by airway remodelling, inflammation, and mucus production. Airway macrophages' functions are underpinned by changes in cellular metabolism. The TCA cycle‐derived metabolite itaconic acid (whose synthesis is mediated by aconitate decarboxylase) is a master regulator of macrophage function; however, its role during inhaled allergen challenge is not clear. The objective of this study was to define the role of itaconate during inhaled allergen challenge. Methods: Sputum metabolite levels were measured in participants with mild allergic asthma undergoing allergen inhalation challenge, and in a second cohort, baseline levels in mild, moderate, and severe asthmatics. Airway inflammation, lung function, and bronchoalveolar lavage metabolite levels were assessed in wild‐type and aconitate decarboxylase‐deficient mice, or in mice treated with inhaled itaconate. Results: Allergen inhalation in mild asthmatics led to a significant reduction in sputum itaconate. We found no difference in baseline sputum itaconate levels when comparing healthy controls to mild, moderate, or severe asthmatics. Continuous exposure to aeroallergen in wild type and aconitate decarboxylase‐deficient mice showed no change in disease phenotype after 48 h, 1, 3, or 5 weeks of allergen exposure. Treatment of house dust mite‐exposed mice with inhaled itaconate reduced airway inflammation. Conclusion: Levels of itaconate are altered after allergen challenge in mild asthmatics and in murine models of disease. Itaconate deficiency did not alter house dust mite‐induced pathology at any of the timepoints tested; however, inhaled itaconate ameliorated inflammatory responses to inhaled allergen.

Rationale: Recovery from chronic obstructive pulmonary disease (COPD) exacerbations is heterogeneous and has a profound impact on disease trajectories. Resolution of airway inflammation is an active process that may be driven by specialized proresolving mediators (SPMs). Objectives: We sought to characterize the temporal change in SPMs in the sputum of patients with COPD during exacerbations, their association with exacerbation triggers, and exacerbation recovery. Methods: Participants were recruited from the London COPD Exacerbation Cohort between January 11, 2016, and April 30, 2018. Participants were reviewed at baseline, exacerbation onset, 1 week, 2 weeks, and 6 weeks during their exacerbation recovery. Sputum collection, nasopharyngeal swabs, phlebotomy, quality-of-life questionnaires, and spirometry were performed at each visit. SPMs were measured in sputum by liquid chromatography–tandem mass spectrometry. Respiratory viruses were measured by quantitative PCR and bacteria by microbiological culture. Measurements and Main Results: There were 68 exacerbations during the study period. Median time to symptomatic recovery was 21 days for viral exacerbations, compared with 13 days in nonviral exacerbations (P < 0.001). There was a significant increase in resolvin D1 (RvD1) at exacerbation onset in bacterial exacerbations but not in viral exacerbations. Lower levels of RvD1 were associated with prolonged respiratory symptoms during the 1-week and 2-week recovery time points. Exogenous RvD1 significantly reduced IL-6 and CXCL8 response to rhinovirus infection in COPD bronchial epithelial cells. Conclusions: There is a dynamic temporal change in airway SPMs during COPD exacerbations. Reduced levels of RvD1 were associated with prolonged respiratory symptoms. SPMs may be a potential therapeutic approach to promote exacerbation recovery.

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.

Idiopathic pulmonary fibrosis (IPF) is a chronic debilitating lung disease, characterised by progressive deposition of excessive extracellular matrix in the lung parenchyma [1]. Though rare, IPF has a median untreated survival of 3 years from diagnosis, making it more deadly than many cancers [2, 3]. Two antifibrotic therapies, pirfenidone and nintedanib, have been shown to effectively slow IPF progression, but neither stop or reverse fibrogenesis [3]. Thus, there is an urgent unmet clinical need to develop more effective treatments for IPF and identify biomarkers.