Pulmonary fibrosis is considered to be one of the most irreversible forms of fibrosis across different organs, despite the lung possessing potent reparative capacity. Idiopathic pulmonary fibrosis (IPF) is the most common and fatal form, inexorably progressing to secondary respiratory failure, with a median survival of 3–5 years from diagnosis (Podolanczuk et al., 2023b). While the aetiology of IPF remains elusive, current thinking revolves around a complex interplay between genetic predisposition and environmental exposures in predominantly elderly male individuals, leading to chronic progressive pulmonary fibrosis (PPF) (Raghu et al., 2022b) (Fig. 1). The most well studied genetic risk factors include genes associated with epithelial function, such as MUC5B (mucin 5B) and SFTPC (surfactant protein C), genes responsible for maintaining telomere homeostasis, such as TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component), genes associated with the immune system, e.g. TOLLIP (toll-interacting protein) or the inflammasome e.g. DPP9 (dipeptidyl peptidase 9), and with cell-cell adhesion, like DSP (desmoplakin), or the RhoA pathway, like AKAP13 (A-kinase anchoring protein 13) among others (Allen et al., 2017; Fingerlin et al., 2013; Mathai et al., 2016; Noth et al., 2013). More recently, a genetic locus associated with DEPTOR, a gene involved in several cellular functions including negative regulation of mTOR (mechanistic target of rapamycin), has also been associated with increased risk of developing IPF (Allen et al., 2020). Environmental factors linked to IPF pathogenesis include cigarette smoke, occupational exposure to certain substances in the workplace, such as wood, metal and silica dust, air pollution, particularly particulate matter and nitrogen dioxide, gastroesophageal reflux disease (GERD) and viral infections (Raghu and Meyer, 2012; Wolters et al., 2018).

The picture remains complex at a cellular level, where IPF is characterised by micro-anatomical redistribution and dysfunction of several cell types. In terms of cell composition, the distal parenchyma in IPF, is enriched with epithelial cell populations that typically reside in the airways. Aberrant basaloid cells have recently been identified as a unique epithelial feature of IPF (and chronic obstructive pulmonary disease) expressing basal cell, senescence and epithelial to mesenchymal transdifferentiation (EMT) markers and appear to overlay fibrotic foci (also known as fibroblastic foci), the histological hallmark of the disease (Adams et al., 2020). Fibrotic foci comprise activated and hyper-synthetic fibroblasts and myofibroblasts embedded in a collagen-rich extracellular matrix (Kuhn and McDonald, 1991). Peribronchial vascular endothelial cells, normally restricted to the bronchial circulation, are observed in areas of remodelling and aberrant angiogenesis (Adams et al., 2020). Type 2 alveolar epithelial cells (AEC2), the stem cell progenitors of the adult lung, display evidence of senescence, with shortened telomeres and a compromised ability to regenerate a functional alveolar epithelium that is able to support efficient gas exchange (Platé et al., 2021). Senescence is also a feature of IPF fibroblasts which are further resistant to apoptosis and unable to efficiently support epithelial regeneration (Alvarez et al., 2017; Ng-Blichfeldt et al., 2019; Ramos et al., 2001). In terms of the IPF immune cell compartment, profibrotic macrophage populations dominate the immune cell landscape in IPF (Adams et al., 2020; Habermann et al., 2020). These together with T cells, may secrete profibrotic and inflammatory cytokines which further promotes the recruitment of other immune cells. B cells have also been found to accumulate in the IPF lung and produce antibodies against self-antigens, suggesting that autoimmunity may be a feature and also play a role in the disease (Desai et al., 2018). The spatially and temporally heterogenous cellular landscape of the IPF lung is therefore complex and future therapies will need to potentially target multiple cellular mechanisms.

Since being first described almost 80 years ago, considerable advances have been made in the diagnosis and prognosis of IPF. The current diagnostic guidelines recommend the use of a combination of clinical evaluation, high resolution computer tomography (HRCT) imaging, and non-invasive tests, such as pulmonary function tests and blood tests, for most cases (Raghu et al., 2018a). In IPF, patients present with a definite or probable usual interstitial pneumonia (UIP) pattern on HRCT. A definite UIP pattern is characterised by reticulation and honeycombing, with or without traction bronchiectasis in a predominantly subpleural and basal distribution (Podolanczuk et al., 2023b). The standard method of assessing severity and response to treatment is lung function, including forced expiratory volume (FEV1), forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO). While surgical lung biopsies (SLB) are recommended in specific and limited cases (Raghu et al., 2018a), in 2022, a conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to SLB in centres with appropriate expertise (Raghu et al., 2022b).

In terms of the development of anti-fibrotic therapeutics, the approval of two agents, pirfenidone (Esbriet) and nintedanib (Ofev), which slow disease progression, represented a turning point for the treatment of IPF. However, these two drugs do not halt or reverse the disease and present considerable side effects (Pleasants and Tighe, 2019), so that new therapeutic approaches are urgently required. Nintedanib/Ofev, is now approved for the treatment of progressive pulmonary fibrosis (PPF), where progression is assessed by a combination of worsening radiological, lung function and symptomatic parameters.

Recently, the James Lind Alliance, a priority setting partnership bringing together patients, carers and clinicians, has published the top 10 priorities in PPF. These include improvement in accuracy and time taken in the diagnosis of PPF and the development of new treatments that can slow, halt or reverse disease progression, convey fewer side effects and importantly improve survival (https://www.jla.nihr.ac.uk/priority-setting-partnerships/progressive-pulmonary-fibrosis/). In this review, we will describe emerging strategies that have the potential to be transformative for the future diagnosis and treatment of IPF.