Idiopathic pulmonary fibrosis (IPF) represents a chronic progressive fibrotic interstitial lung disease of unknown cause with an ominous prognosis. It remains an unprecedent clinical challenge due to its delayed diagnosis and unpredictable clinical course. The need for accurate diagnostic, prognostic and predisposition biomarkers in everyday clinical practice becomes more necessary than ever to ensure prompt diagnoses and early treatment. The identification of such blood biomarkers may also unravel novel drug targets against IPF development and progression. So far, the role of diverse blood biomarkers, implicated in various pathogenetic pathways, such as in fibrogenesis (S100A4), extracellular matrix remodelling (YKL-40, MMP-7, ICAM-1, LOXL2, periostin), chemotaxis (CCL-18, IL-8), epithelial cell injury (KL-6, SP-A, SP-D), autophagy and unfolded protein response has been investigated in IPF with various results. Moreover, the recent progress in genetics in IPF allows for a better understanding of the underlying disease mechanisms. So far, the causative mutations in pulmonary fibrosis include mutations in telomere-related genes and in surfactant-related genes, markers that could act as predisposition biomarkers in IPF. The aim of this review is to provide a comprehensive overview from the bench to bedside of current knowledge and recent insights on biomarkers in IPF, and to suggest future directions for research. Large-scale studies are still needed to confirm the exact role of these biomarkers.

Background: Urban air pollution is involved in the progress of idiopathic pulmonary fibrosis (IPF). Its potential role on the devastating event of Acute Exacerbation of IPF (AE-IPF) needs to be clarified. This study examined the association between long-term personal air pollution exposure and AE- IPF risk taking into consideration inflammatory mediators and telomere length (TL). Methods: All consecutive IPF-patients referred to our Hospital from October 2013-June 2019 were included. AE-IPF events were recorded and inflammatory mediators and TL measured. Long-term personal air pollution exposures were assigned to each patient retrospectively, for O₃, NO₂, PM_2.5 [and PM₁₀, based on geo-coded residential addresses. Logistic regression models assessed the association of air pollutants’ levels with AE-IPF and inflammatory mediators adjusting for potential confounders. Results: 118 IPF patients (mean age 72 ± 8.3 years) were analyzed. We detected positive significant associations between AE-IPF and a 10 μg/m³ increase in previous-year mean level of NO₂ (OR = 1.52, 95%CI:1.15–2.0, p = 0.003), PM_2.5 (OR = 2.21, 95%CI:1.16–4.20, p = 0.016) and PM₁₀ (OR = 2.18, 95%CI:1.15–4.15, p = 0.017) independent of age, gender, smoking, lung function and antifibrotic treatment. Introduction of TL in all models of a subgroup of 36 patients did not change the direction of the observed associations. Finally, O₃ was positively associated with %change of IL-4 (p = 0.014) whilst PM_2.5, PM₁₀ and NO₂ were inversely associated with %changes of IL-4 (p = 0.003, p = 0.003, p = 0.032) and osteopontin (p = 0.013, p = 0.013, p = 0.085) respectively. Conclusions: Long-term personal exposure to increased concentrations of air pollutants is an independent risk factor of AE-IPF. Inflammatory mediators implicated in lung repair mechanisms are involved.

Introduction: Post-acute sequelae of COVID-19 seem to be an emerging global crisis. Machine learning radiographic models have great potential for meticulous evaluation of post-COVID-19 interstitial lung disease (ILD).Methods: In this multicenter, retrospective study, we included consecutive patients that had been evaluated 3 months following severe acute respiratory syndrome coronavirus 2 infection between 01/02/2021 and 12/5/2022. High-resolution computed tomography was evaluated through Imbio Lung Texture Analysis 2.1.Results: Two hundred thirty-two (n = 232) patients were analyzed. FVC% predicted was ≥80, between 60 and 79 and <60 in 74.2% (n = 172), 21.1% (n = 49), and 4.7% (n = 11) of the cohort, respectively. DLCO% predicted was ≥80, between 60 and 79 and <60 in 69.4% (n = 161), 15.5% (n = 36), and 15.1% (n = 35), respectively. Extent of ground glass opacities was ≥30% in 4.3% of patients (n = 10), between 5 and 29% in 48.7% of patients (n = 113) and <5% in 47.0% of patients (n = 109). The extent of reticulation was ≥30%, 5–29% and <5% in 1.3% (n = 3), 24.1% (n = 56), and 74.6% (n = 173) of the cohort, respectively. Patients (n = 13, 5.6%) with fibrotic lung disease and persistent functional impairment at the 6-month follow-up received antifibrotics and presented with an absolute change of +10.3 (p = 0.01) and +14.6 (p = 0.01) in FVC% predicted at 3 and 6 months after the initiation of antifibrotic.Conclusion: Post-COVID-19-ILD represents an emerging entity. A substantial minority of patients presents with fibrotic lung disease and might experience benefit from antifibrotic initiation at the time point that fibrotic-like changes are “immature.” Machine learning radiographic models could be of major significance for accurate radiographic evaluation and subsequently for the guidance of therapeutic approaches.

Short telomeres are recognized as risk factor for idiopathic pulmonary fibrosis (IPF). We aimed to assess the role of telomere length (TL) in fibrotic-Interstitial Lung Diseases (f-ILDs) associated with a usual interstitial pneumonia (UIP) pattern as well as in IPF acute exacerbation (IPF-AE). TL was measured from peripheral white blood cells using a multiplex quantitative polymerase chain reaction in consecutive patients with f-ILDs, all presenting UIP pattern in the high-resolution chest-computed-tomography and compared to age-matched healthy controls. Seventy-nine individuals were included (mean age 69.77 ± 0.72 years); 24 stable IPF, 18 IPF-AE, 10 combined pulmonary fibrosis and emphysema, 7 Rheumatoid arthritis-UIP-ILDs and 20 controls. TL in all patients was significantly shorter compared to controls [mean T/S ratio (SE) 0.77 (±0.05) vs 2.26 (±0.36), p < 0.001] as well as separately in each one of f-ILD subgroups. IPF-AE patients presented significantly shorter TL compared to stable IPF (p = 0.029). Patients with IPF and shorter than the median TL (0-0.72) showed reduced overall survival (p = 0.004). T/S < 0.72 was associated with increased risk for IPF-AE (OR = 30.787, 95% CI: 2.153, 440.183, p = 0.012) independent of age, gender, smoking and lung function impairment. A protective effect of TL was observed, as it was inversely associated with risk of death both in UIP-f-ILDs (HR = 0.174, 95%CI: 0.036, 0.846, p = 0.030) and IPF patients (HR = 0.096, 95%CI: 0.011, 0.849, p = 0.035). Shorter TL characterizes different UIP f-ILDs. Although no difference was observed in TL among diverse UIP subgroups, IPF-AE presented shorter TL compared to stable IPF. Reduced overall survival and higher hazard ratio of death are associated with shorter TL in IPF.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with a dismal prognosis. While the standard-of-care (SOC) drugs approved for IPF represent a significant advancement in antifibrotic therapies, they primarily slow disease progression and have limited overall efficacy and many side effects. Consequently, IPF remains a condition with high unmet medical and pharmacological needs. A wide variety of molecules and mechanisms have been implicated in the pathogenesis of IPF, many of which have been targeted in clinical trials. In this review, we discuss the latest therapeutic targets that affect extracellular matrix (ECM) homeostasis and the activation of lung fibroblasts, with a specific focus on ECM invasion. A promising new approach involves targeting ECM invasion by fibroblasts, a process that parallels cancer cell behavior. Several cancer drugs are now being tested in IPF for their ability to inhibit ECM invasion, offering significant potential for future treatments. The delivery of these therapies by inhalation is a promising development, as it may enhance local effectiveness and minimize systemic side effects, thereby improving patient safety and treatment efficacy.