Chronic Fibrosing Interstitial Pneumonia Research Articles

Prognostic performance of Krebs von den Lungen-6, surfactant protein A, surfactant protein D levels in the serum and bronchoalveolar lavage fluid in chronic fibrosing interstitial pneumonia: a retrospective study

BackgroundThe serum markers Krebs von den Lungen-6 (KL-6), surfactant protein A (SP-A), and surfactant protein D (SP-D) have been used for the diagnosis, differential diagnosis, and prognosis prediction of interstitial pneumonia. However, the significance of measuring the serum and bronchoalveolar lavage fluid (BALF) KL-6, SP-D, and SP-A levels in predicting the prognosis of chronic fibrosing interstitial pneumonia (CFIP), idiopathic pulmonary fibrosis, and idiopathic nonspecific interstitial pneumonia remains unclear. We aimed to clarify the significance of measuring the serum and BALF KL-6, SP-A, and SP-D levels in predicting the prognosis of patients with CFIP.MethodsAmong 173 patients who were diagnosed with CFIP between September 2008 and February 2021, 39 who underwent bronchoalveolar lavage were included in this study. Among these, patients experiencing an annual decrease in forced vital capacity (FVC) of ≥10% or those facing challenges in undergoing follow-up pulmonary function tests owing to significant deterioration in pulmonary function were categorized as the rapidly progress group. Conversely, individuals with an annual decrease in the FVC of <10% were classified into the slowly progress group. The serum and BALF KL-6, SP-D, and SP-A levels, as well as BALF/serum SP-D and SP-A ratios were compared between the two groups.ResultsAmong the patients with CFIP, the BALF SP-D level (p=0.0111), BALF SP-A level (p<0.0010), BALF/serum SP-D ratio (p=0.0051), and BALF/serum SP-A ratio (p<0.0010) were significantly lower in the rapidly than in the slowly progress group (p<0.0010). The receiver operating characteristics analysis results demonstrated excellent performance for diagnosing patients with CFIP, with the BALF SP-D level (area under the curve [AUC], 0.7424), BALF SP-A level (AUC, 0.8842), BALF/serum SP-D ratio (AUC, 0.7673), and BALF/serum SP-A ratio (AUC, 0.8556). Moreover, the BALF SP-A level showed a notably superior CFIP diagnostic capability. Survival analysis using the Kaplan–Meier method revealed that patients with a BALF SP-A level of <1500 ng/mL and BALF/serum SP-A ratio of <15.0 had poor prognoses.ConclusionsOur results suggest that BALF SP-A measurement may be useful for predicting the prognosis in patients with CFIP.

Features of the course of idiopathic fibrosing alveolitis

Idiopathic pulmonary fibrosis (IPF) is a special form of chronic progressive fibrosing interstitial pneumonia of unknown etiology; it occurs predominantly in elderly people, affects only the lungs, and is associated with the histological and/or radiological pattern of common interstitial pneumonia. The frequency of this pathology has been increasing in recent years. A timely diagnosis and treatment can slow down the progression of the disease and prevent the need for lung transplantation.

Hypersensitivity pneumonitis: Principles in diagnosis and management.

Hypersensitivity pneumonitis: Principles in diagnosis and management.

Short Telomere Syndrome presenting with pulmonary fibrosis, liver cirrhosis and hepatopulmonary syndrome: a case report

BackgroundIdiopathic pulmonary fibrosis is thought to result from aberrant post-injury activation of epithelial cells leading to fibroblast proliferation and activation. A number of genetic aetiologies have been implicated in this disease process, including, among others, the short telomere syndromes. Short telomere syndromes follow an autosomal dominant pattern of inheritance resulting in shortened telomere length, which consequently leads to accelerated cell death. Organs with rapid cell turnover are most affected.Case presentationWe describe a case of a 53-year-old man with a chief complaint of cough and dyspnea on exertion. His presentation was otherwise significant for features of accelerated aging, including a history of osteoporosis and early greying, and a family history of pulmonary fibrosis in his father. Pulmonary function testing revealed a restrictive pattern with severely reduced diffusion capacity and high resolution CT of the chest showed diffuse lung disease with mild fibrosis, in pattern suggesting an alternative diagnosis to IPF. Biopsy of the lung was in keeping with chronic fibrosing interstitial pneumonia. Imaging of the abdomen showed splenomegaly, hepatic cirrhosis and portal hypertension. Transthoracic contrast echocardiogram showed intrapulmonary shunting consistent with hepatopulmonary syndrome. Given the constellation of early aging, idiopathic pulmonary fibrosis, cryptogenic cirrhosis and a family history of pulmonary fibrosis in this patient, the Short Telomere Syndrome was suspected. Peripheral blood was sent for Flow-cytometry FISH, which demonstrated granulocyte telomere length below the 10th percentile for the patient’s age, consistent with a diagnosis of Short Telomere Syndrome in this clinical context. Targeted genetic testing of mutations known to be associated with short telomere was negative though it was acknowledged that the full spectrum of disease-causing mutations remains unknown. Given the extensive fibrosis on biopsy and his progressive hypoxemia he was treated with mycophenolate and prednisone. Ultimately, he developed progressive respiratory failure and underwent double lung and concurrent liver transplant 18 months after the initial diagnosis was made.ConclusionsShort Telomere Syndrome is a rare cause of end stage organ disease and testing lacks sensitivity making diagnosis challenging. Organ transplant is still the mainstay of treatment. Nevertheless, disease identification is important because of implications for family member screening and the possibility of future treatment options.

Impaired Dynamic Response of Oxygen Saturation During the 6-min Walk Test Is Associated With Mortality in Chronic Fibrosing Interstitial Pneumonia.

The 6-min walk test (6MWT) is a common assessment of exercise-induced hypoxemia and exercise capacity used in patients with chronic fibrosing interstitial pneumonia (CFIP). However, whether the dynamic changes in SpO2 and heart rate during the 6MWT are associated with mortality in patients with CFIP has been undefined. This retrospective study enrolled 63 subjects with mild to severe CFIP who underwent the 6MWT. Subjects with CFIP were divided into 2 groups according to disease severity: mild, diffusing capacity of the lungs for carbon monoxide percentage predicted (%DLCO) > 55% and %FVC > 75%; and severe, %DLCO ≤ 55% and/or %FVC ≤ 75%. This study aimed to evaluate dynamic changes in the 6MWT including 6-min walk distance, change in SpO2 (ΔSpO2 ), SpO2 reduction time, SpO2 recovery time, change in heart rate (Δ heart rate), heart rate acceleration time, slope of heart rate acceleration, heart rate recovery at 1 min of rest after the 6MWT (HR-recovery), and dyspnea on exertion that are reflected by static pulmonary function and are related to exacerbation of CFIP and mortality. Compared with subjects with mild CFIP, subjects with severe CFIP had significantly larger ΔSpO2 and longer SpO 2 reduction time and recovery time. The slope of heart rate, heart rate immediately after the 6MWT, and HR-recovery were lower in subjects with severe CFIP than in those with mild CFIP. In multiple regression analysis, percent vital capacity was significantly associated with SpO2 reduction time, and %DLCO was significantly associated with ΔSpO2 and SpO2 recovery time. Subjects with ΔSpO2 of > 10% and SpO2 recovery time of > 79 s had a significantly higher risk for exacerbation and mortality. Dynamic changes in SpO2 and heart rate during the 6MWT were associated with risk for exacerbation and mortality in subjects with CFIP. Impaired dynamic response of SpO2 could reflect likelihood of exacerbation and increased mortality in CFIP.

Combination of computed tomography imaging pattern and severity of respiratory failure as factors associated with prognosis for acute exacerbation of idiopathic chronic fibrosing interstitial pneumonia.

The prognosis of idiopathic chronic fibrotic interstitial pneumonitis (CFIP) in patients with acute exacerbation (AE) is variable. We examined whether the imaging pattern on thoracic computed tomography (CT) or the severity of respiratory failure with AE-CFIP is associated with short-term prognosis. Patients admitted to two university hospitals were retrospectively analyzed and divided into derivation and validation cohorts. The distribution of newly appearing parenchymal abnormalities on thoracic CT was classified into peripheral, multifocal, and diffuse patterns. Respiratory failure was defined as severe if a fraction of inspired oxygen ≥ 0.5 was required to maintain percutaneous oxygen saturation ≥ 90% on admission. Factors associated with 90 day-mortality were analyzed using univariate and Cox proportional hazard regression. In 59 patients with AE-CFIP of the derivation cohort, diffuse pattern on CT was associated with higher mortality within 90 days (43%) than peripheral/multifocal pattern (17%, p = 0.03). Additionally, compared with non-severe failure, severe respiratory failure was associated with higher mortality (47% vs. 21%, p = 0.06). Cox proportional hazard regression analysis demonstrated that a combination of diffuse pattern on CT and severe respiratory failure was associated with the poorest prognosis (hazard ratio [HR] 3.51 [interquartile range 1.26-9.80], p = 0.016) in the derivation cohort, which was confirmed in the validation cohort (n = 31, HR 4.30 [interquartile range 1.51-12.2], p = 0.006). The combination of imaging pattern on thoracic CT and severity of respiratory failure was associated with the prognosis of idiopathic AE-CFIP.

BAL Proteomic Signature of Lung Adenocarcinoma in IPF Patients and Its Transposition in Serum Samples for Less Invasive Diagnostic Procedures.

Idiopathic pulmonary fibrosis (IPF) is a form of chronic and irreversible fibrosing interstitial pneumonia of unknown etiology. Although antifibrotic treatments have shown a reduction of lung function decline and a slow disease progression, IPF is characterize by a very high mortality. Emerging evidence suggests that IPF increases the risk of lung carcinogenesis. Both diseases show similarities in terms of risk factors, such as history of smoking, concomitant emphysema, and viral infections, besides sharing similar pathogenic pathways. Lung cancer (LC) diagnosis is often difficult in IPF patients because of the diffuse lung injuries and abnormalities due to the underlying fibrosis. This is reflected in the lack of optimal therapeutic strategies for patients with both diseases. For this purpose, we performed a proteomic study on bronchoalveolar lavage fluid (BALF) samples from IPF, LC associated with IPF (LC-IPF) patients, and healthy controls (CTRL). Molecular pathways involved in inflammation, immune response, lipid metabolism, and cell adhesion were found for the dysregulated proteins in LC-IPF, such as TTHY, APOA1, S10A9, RET4, GDIR1, and PROF1. The correlation test revealed a relationship between inflammation- and lipid metabolism-related proteins. PROF1 and S10A9, related to inflammation, were up-regulated in LC-IPF BAL and serum, while APOA1 and APOE linked to lipid metabolism, were highly abundant in IPF BAL and low abundant in IPF serum. Given the properties of cytokine/adipokine of the nicotinamide phosphoribosyltransferase, we also evaluated its serum abundance, highlighting its down-regulation in LC-IPF. Our retrospective analyses of BAL samples extrapolated some potential biomarkers of LC-IPF useful to improve the management of these contemporary pathologies. Their differential abundance in serum samples permits the measurement of these potential biomarkers with a less invasive procedure.

Pre-exposure to Aerosolized Polyvalent Bacterial Lysates Protects Against Bleomycin-Induced Pulmonary Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause. No therapeutic modalities can reverse or stop its ever-deteriorating course. The stimulation of lung innate immunity using bacterial lysates was found to protect against lethal pulmonary infection. Hence, this study aimed to explore whether the immune-stimulating enhancement by pretreatment with bacterial lysates led to protection against bleomycin-induced pulmonary fibrosis. C57BL/6 mice were randomly divided into 4 groups with 20 mice in each group. The mice were exposed to an aerosolized mixture of polyvalent bacterial lysates (PVBL) or phosphate-buffered saline (PBS) three times on separate days. Twenty-four hours after the last exposure, the lungs were intratracheally infused with bleomycin (BLM) or normal saline (NS). The pulmonary morphology, Ashcroft's scale of pulmonary fibrosis, and levels of pro-inflammatory cytokines such as interferon (IFN)-γ and interleukin (IL)-4 were evaluated 14 days after the intratracheal infusion. The exposure to PVBL did not induce any discernible structural abnormalities in the lungs, while the IFN-γ/IL-4 ratio increased. BLM-induced pulmonary fibrosis was associated with an overwhelming downregulation of IFN-γ and IL-4 expression. Pre-exposure to PVBL protected against BLM-induced pulmonary fibrosis, which was demonstrated by a greater reduction of Ashcroft's fibrotic score and a greater decrease in the hydroxyproline level in the lungs. Although the PVBL pre-exposure did not restore the BLM-induced downregulation of IL-4 and IFN-γ levels, the IFN-γ/IL-4 ratio was still maintained greater than the animals with BLM infusion. BLM-induced murine pulmonary fibrosis is associated with downregulation of IFN-γ and IL-4 levels. Pre-exposure to the aerosolized PVBL protects against BLM-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis in the practice of a family doctor

Idiopathic pulmonary fibrosis (IPF) is a disease of unknown etiology, mainly characterized by a progressive deterioration in lung function due to active fibrosis. It is a variant of chronic progressive fibrosing interstitial pneumonia. The disease most often occurs between the ages of 50 and 70. According to the disease register in the Russian Federation, the prevalence of the disease in the Russian Federation is 4-7 people per hundred thousand of the population [1].Worldwide, the IPF incidence, prevalence and mortality increases over time [2, 3]. In a systematic review of the study by Hutchinson et al. [2] based on data on IPF morbidity and mortality in 21 countries between 1968 and 2012, it was determined that both morbidity and mortality have increased worldwide since 2000.

KL-6 as an Immunological Biomarker Predicts the Severity, Progression, Acute Exacerbation, and Poor Outcomes of Interstitial Lung Disease: A Systematic Review and Meta-Analysis.

ObjectInterstitial lung disease (ILD) is a specific form of chronic fibrosing interstitial pneumonia with various etiology. The severity and progression of ILD usually predict the poor outcomes of ILD. Otherwise, Krebs von den Lungen-6 (KL-6) is a potential immunological biomarker reflecting the severity and progression of ILD. This meta-analysis is to clarify the predictive value of elevated KL-6 levels in ILD.MethodEBSCO, PubMed, and Cochrane were systematically searched for articles exploring the prognosis of ILD published between January 1980 and April 2021. The Weighted Mean Difference (WMD) and 95% Confidence Interval (CI) were computed as the effect sizes for comparisons between groups. For the relationship between adverse outcome and elevated KL-6 concentration, Hazard Ratio (HR), and its 95%CI were used to estimate the risk factor of ILD.ResultOur result showed that ILD patients in severe and progressive groups had higher KL-6 levels, and the KL-6 level of patients in the severe ILD was 703.41 (U/ml) than in mild ILD. The KL-6 level in progressive ILD group was 325.98 (U/ml) higher than that in the non-progressive ILD group. Secondly, the KL-6 level of patients in acute exacerbation (AE) of ILD was 545.44 (U/ml) higher than stable ILD. Lastly, the higher KL-6 level in ILD patients predicted poor outcomes. The KL-6 level in death of ILD was 383.53 (U/ml) higher than in survivors of ILD. The pooled HR (95%CI) about elevated KL-6 level predicting the mortality of ILD was 2.05 (1.50–2.78), and the HR (95%CI) for progression of ILD was 1.98 (1.07–3.67).ConclusionThe elevated KL-6 level indicated more severe, more progressive, and predicted the higher mortality and poor outcomes of ILD.

P16‐93: Preliminary analysis of serum risk factors during an acute exacerbation of chronic fibrosing interstitial pneumonia: A multi‐institutional prospective study

P16‐93: Preliminary analysis of serum risk factors during an acute exacerbation of chronic fibrosing interstitial pneumonia: A multi‐institutional prospective study

P16‐73: Prognostic significance of serum serological and radiological findings in idiopathic chronic fibrosing interstitial pneumonia

P16‐73: Prognostic significance of serum serological and radiological findings in idiopathic chronic fibrosing interstitial pneumonia

Идиопатический легочный фиброз в практике врача-терапевта

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic progressive fibrosing interstitial pneumonia of unknown etiology that affects only the lungs and is associated with the histological and / or radiological pattern of common interstitial pneumonia. The clinical substrate for IPF is progressive dyspnea and dry cough. The characteristic auscultatory sign of IPF is inspiratory crepitus. Fibrosis is an important morphological component of IPF. The leading CT sign of IPF is a “honeycomb” lung (local air cysts located subpleurally and having similar sizes from 2–3 to 10 mm with clearly delineated walls). Mostly people over 60 years old are ill, often smokers, or with a history of smoking. In 60% of patients, the course of IPF is progressive, death within 5 years in 40% of cases. In 30–50% of cases, IPF requires the exclusion of other forms of interstitial lung disease. To date, it has been established that the basic drugs in the treatment of IPF with proven efficacy are nintedanib and pirfenidone. This article presents a clinical case of idiopathic pulmonary fibrosis in a 63-year-old patient who was hospitalized in the pulmonology department. The given example justifies the need for increased vigilance among pulmonologists and general practitioners when interpreting the clinical manifestations of the disease.

Association of serum monomeric periostin level with outcomes of acute exacerbation of idiopathic pulmonary fibrosis and fibrosing nonspecific interstitial pneumonia.

BackgroundThe associations of serum monomeric periostin (M-PN) level and serial change in M-PN with acute exacerbation of chronic fibrosing interstitial pneumonia (AE-FIP) are unclear.MethodsWe prospectively measured serum M-PN level from onset of AE to day 14 in 37 patients with AE-FIP and evaluated its association with outcome. To determine localization of periostin expression, immunohistochemical staining of pathological lung tissue from autopsy cases of AE-IPF was evaluated.ResultsData from 37 AE-FIP patients (28 men; age 73.9±7.8 years) were analyzed. With healthy controls as reference, serum M-PN level was significantly higher in patients with AE-FIP (P=0.02) but not in those with stable idiopathic pulmonary fibrosis (P=1.00). M-PN was significantly lower on day 7 than at AE-FIP onset in survivors [14.6±5.8 vs. 9.3±2.8 ng/mL (onset to day 7: P<0.001)] but not in non-survivors [14.6±5.1 vs. 13.2±5.1 ng/mL (onset to day 7: P=0.07)]. In analysis using a cut-off value for serial change in M-PN (ΔM-PN), 3-month survival was 92.3% in the ΔM-PN decrease group and 36% in the ΔM-PN increase group (P=0.002). In multivariate analysis, 3-month survival tended to be associated with high ΔM-PN (OR: 12.4, 95% CI: 0.82–187.9, P=0.069).ConclusionsSerial change in serum M-PN level may be a prognostic indicator of AE-FIP.

The prognostic value of fixed time and self-paced walking tests in patients diagnosed with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic fibrosing interstitial pneumonia that has an unknown etiology. The natural history of the disease is characterized by a progressive decline in pulmonary function and overall health and well-being. The median survival time is between 2-3 years; however, the disease course is variable and unpredictable. The twelve-minute walking test (12MWT) and six-minute walking test (6MWT) are two fixed time tests that are commonly used in clinical practice. Our short and clinically oriented narrative review attempted to summarize current evidence supporting the use of fixed time, self-paced walking tests in predicting the outcome of patients diagnosed with IPF. A number of studies have justified that the 6MWT is a simple, cost-effective, well documented, fixed time, and self-paced walking test which is a valid and reliable measure of disease status and can also be used as a prognostic tool in patients with IPF. However, there is a need for dedicated and validated reference equations for this population of patients. It is also necessary to fill the knowledge gap about the role of the 12MWT. We hypothesize that it would be useful in evaluating patients that are in the early stages of the disease.

Inter-observer agreement in identifying traction bronchiectasis on computed tomography: its improvement with the use of the additional criteria for chronic fibrosing interstitial pneumonia.

To assess inter-observer variability in identifying traction bronchiectasis on computed tomography (CT) using additional criteria for chronic fibrosing interstitial pneumonia. Seven experts categorized CT image set representing 39 patients into three groups on the basis of the presence of traction bronchiectasis, using a three-point scale: 3-definitely/probably yes; 2-possibly yes; and 1-definitely/probably no. This scale served as a reference standard. The image set included cases of chronic fibrosing interstitial pneumonia, non-interstitial lung disease, and difficult-to-determine cases. Forty-eight observers similarly assessed the same image set, first according to the Fleischner Society definition, and second with additional criteria, in which traction bronchiectasis was observed exclusively in chronic fibrosing interstitial pneumonia. The agreement level between the reference standard and each observer's evaluation in each session was calculated using weighted kappa values which were compared between the two sessions using a paired t test. The mean weighted kappa value for all observers was significantly higher in the second reading session (mean 0.75) than in the first reading session (mean 0.62) (p < 0.001). Inter-observer agreement in identifying traction bronchiectasis improves when using the additional criteria which specify chronic fibrosing interstitial pneumonia as the underlying disease.

Acute exacerbation of chronic fibrosing interstitial pneumonia in patients receiving antifibrotic agents: incidence and risk factors from real-world experience

Background and objectiveHere, we present real-world data on the incidence and risk factors of acute exacerbation (AE) in patients with chronic fibrotic interstitial pneumonia (CFIP) treated with antifibrotic agents, which has been previously poorly documented.MethodsWe retrospectively examined clinical characteristics, incidence and risk factors of AE in a cohort of 100 patients with CFIP (n = 75, idiopathic pulmonary fibrosis [IPF]; n = 25, other conditions), all of whom received antifibrotic agents in a real-world setting.ResultsThe median follow-up was 17.4 months (interquartile range [IQR], 6.6 to 26.7 months). During the follow-up periods, 21 patients experienced AE after starting antifibrotic agents. The estimated 1-, 2-, and 3-year AE incidence rates were 11.4% (95% confidence interval [95%CI], 6.2–20.3%), 32% (95%CI, 20.7–47.4%), and 36.3% (95%CI 23.5–53.1%), respectively. Decreased baseline lung function (forced vital capacity and carbon monoxide diffusing capacity of the lung), existence of pulmonary hypertension estimated from an echocardiogram, higher Interstitial Lung Disease-Gender, Age, and Physiology (ILD-GAP) score, supplementary oxygen, and concomitant corticosteroid and proton-pump inhibitor (PPI) use upon starting the antifibrotic agent were risk factors of AE. Concomitant corticosteroid and PPI use and corticosteroid dose were risk factor of AE in a multivariate Cox regression hazard model adjusting for ILD-GAP score.ConclusionAE of CFIP is more common in patients with physiologically and functionally advanced disease under antifibrotic agents. Prudent use of corticosteroids and PPIs when initiating antifibrotic agents may be recommended. Further studies are warranted.

Prognostic factors for acute exacerbation of idiopathic pulmonary fibrosis: protocol for a systematic review and meta-analysis

IntroductionIdiopathic pulmonary fibrosis (IPF) is a form of chronic fibrosing interstitial pneumonia with unknown disease aetiology. Acute exacerbation (AE) of IPF is an accelerated disease progression beyond its expected course....

Cyclosporin A in idiopathic chronic fibrosing interstitial pneumonia without idiopathic pulmonary fibrosis.

We have sometimes observed interstitial pneumonia which had chronic course and unknown causes but not diagnosed as idiopathic pulmonary fibrosis (IPF). However, the treatment strategy was not established definitely. To clarify the usefulness of cyclosporin A (CsA) in idiopathic chronic fibrosing interstitial pneumonia (iCFIP) without IPF, we examined longitudinal changes in pulmonary physiology. Japanese patients with iCFIP without IPF treated with CsA were identified retrospectively. Linear mixed-effects models were used to evaluate changes in pulmonary physiology after adjusting for age, sex, and smoking history. Primary outcomes were longitudinal trajectories of the percent predicted forced vital capacity (%FVC), percent predicted diffusing capacity for carbon monoxide (%DLco), and composite physiologic index (CPI) before and after CsA. Thirty-three patients were included. Before CsA initiation, %FVC, %DLco, and CPI declined at rates of 9.1%, 8.6% and -7.1 per 1 year, respectively. After CsA initiation, the gradient of %FVC showed significant improvements in 0-1 years (6.2%±3.0%; P<0.01) and in 1-2 years (10.0%±3.6%; P<0.01); %DLco improved in 0-1 year (4.0%±4.6%; P=0.09) and in 1-2 years (7.0%±5.6%; P=0.02); and CPI improved in 0-1 year (3.2%±3.3%; P=0.06) and in 1-2 years (4.6%±4.1%; P=0.03). CsA for iCFIP without IPF may be associated with improvements in pulmonary physiology in 2 years. Further studies are needed to determine the role of CsA in iCFIP without IPF.

Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause with a median survival of only three years. Little is known about the mechanisms that precede the excessive collagen deposition seen in IPF, but cellular senescence has been strongly implicated in disease pathology. Senescence is a state of irreversible cell-cycle arrest accompanied by an abnormal secretory profile and is thought to play a critical role in both development and wound repair. Normally, once a senescent cell has contributed to wound repair, it is promptly removed from the environment via infiltrating immune cells. However, if immune clearance fails, the persistence of senescent cells is thought to drive disease pathology through their altered secretory profile. One of the major cell types involved in wound healing is fibroblasts, and senescent fibroblasts have been identified in the lungs of patients with IPF and in fibroblast cultures from IPF lungs. The question of what is driving abnormally high numbers of fibroblasts into senescence remains unanswered. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays a role in a myriad of processes, including cell-cycle progression, gene transcription, as well as mitochondrial respiration, all of which are dysregulated during senescence. Activation of STAT3 has previously been shown to correlate with IPF progression and therefore is a potential molecular target to modify early-stage senescence and restore normal fibroblast function. This review summarizes what is presently known about fibroblast senescence in IPF and how STAT3 may contribute to this phenotype.