Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading to fatal diseases. Senescent cells are a main driver of fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report that cellular senescence, and multiple types of fibrotic diseases in mice and humans are characterized by the accumulation of iron. We show that vascular and hemolytic injuries are efficient in triggering iron accumulation, which in turn can cause senescence and promote fibrosis. Notably, we find that senescent cells persistently accumulate iron, even when the surge of extracellular iron has subdued. Indeed, under normal conditions of extracellular iron, cells exposed to different types of senescence-inducing insults accumulate abundant ferritin-bound iron, mostly within lysosomes, and present high levels of labile iron, which fuels the generation of reactive oxygen species and the SASP. Finally, we demonstrate that detection of iron by magnetic resonance imaging might allow non-invasive assessment of fibrotic burden in the kidneys of mice and in patients with renal fibrosis. Our findings suggest that iron accumulation plays a central role in senescence and fibrosis, even when the initiating events may be independent of iron, and identify iron metabolism as a potential therapeutic target for senescence-associated diseases.

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.

(1) The role of the immune response in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains controversial. We hypothesized that peripheral blood immune phenotypes will be different in IPF patients and may relate to the disease severity and progression. (2) Whole blood flow cytometry staining was performed at diagnosis in 32 IPF patients, and in 32 age- and smoking-matched healthy controls. Thirty-one IPF patients were followed up for one year and categorized as stable or progressors based on lung function, deterioration and/or death. At 18–60 months, immunophenotypes were characterized again. (3) The main results showed that: (1) compared to matched controls, at diagnosis, patients with IPF showed more neutrophils, CD8⁺HLA-DR⁺ and CD8⁺CD28⁻ T cells, and fewer B lymphocytes and naïve T cells; (2) in IPF, circulating neutrophils, eosinophils and naïve T cells were associated with lung function abnormalities; (3) patients whose disease progressed during the 12 months of follow-up showed evidence of cytotoxic dysregulation, with increased CD8⁺CD28⁻ T cells, decreased naïve T cells and an inverted CD4/CD8 ratio at baseline; and (4) blood cell alterations were stable over time in survivors. (4) IPF is associated with abnormalities in circulating immune cells, particularly in the cytotoxic cell domain. Patients with progressive IPF, despite antifibrotic therapy, present an over-activated and exhausted immunophenotype at diagnosis, which is maintained over time.

Fibrosing interstitial lung diseases (ILDs) are characterized by the gradual and irreversible accumulation of scar tissue in the lung parenchyma. The role of the immune response in the pathogenesis of pulmonary fibrosis remains unclear. In recent years, substantial advancements have been made in our comprehension of the pathobiology driving fibrosing ILDs, particularly concerning various age-related cellular disturbances and immune mechanisms believed to contribute to an inadequate response to stress and increased susceptibility to lung fibrosis. Emerging studies emphasize cellular senescence as a key mechanism implicated in the pathobiology of age-related diseases, including pulmonary fibrosis. Cellular senescence, marked by antagonistic pleiotropy, and the complex interplay with immunity, are pivotal in comprehending many aspects of lung fibrosis. Here, we review progress in novel concepts in cellular senescence, its association with the dysregulation of the immune response, and the evidence underlining its detrimental role in fibrosing ILDs.

The spectrum of interstitial lung diseases (ILDs) includes a wide range of clinical entities with variable disease courses and prognoses. Several ILDs other than idiopathic pulmonary fibrosis (IPF) may exhibit a progressive fibrotic phenotype, with diverse clinical presentation, histopathological and radiological patterns, as well as varying rates of disease progression and uncertain epidemiology, but with a similar prognosis of untreated idiopathic pulmonary fibrosis with irreversible lung function deterioration, substantial worsening of quality of life and early mortality. The recently defined term “progressive pulmonary fibrosis” (PPF) stands as an opportunity to better classify patients with progressive fibrotic disease and other IPF, irrespective of the underlying ILD. The definition of disease progression, including factors such as pulmonary function test decline, radiological progression, and symptomatic worsening, was not adopted until recently, thus significantly impacting the certainty of current estimates of incidence and prevalence and prognostic outcomes. Understanding disease progression in the broad spectrum of potentially progressive ILDs is key for developing standardized management algorithms irrespective of the ILD diagnosis. Current evidence points towards the potential beneficial effect of antifibrotic drugs in lung function decline and overall outcomes in several non-IPF progressive ILDs showing progression despite optimal management.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy, offering significant efficacy and a generally favorable safety profile. However, they are associated with a spectrum of immune-related adverse events (irAEs), among which pneumonitis stands out due to its relatively high mortality. This condition is characterized by nonspecific clinical manifestations and a broad differential diagnosis, often requiring the involvement of pulmonologists for accurate diagnosis and management. Given its potential severity, it is crucial for pulmonologists to be well-versed in recognizing and addressing checkpoint inhibitor pneumonitis (CIP). In this narrative review, we examine reported cases of pneumonitis in patients with various types of cancer treated with ICIs. The article explores the mechanisms of action of ICIs, the underlying pathophysiology of pneumonitis, associated risk factors, clinical presentation, diagnostic approaches, and current treatment strategies, intended to support pulmonologists in improving early detection and implementing evidence-based management of this potentially life-threatening complication.