Genetic Testing Goes Beyond Imaging and Histological Evaluation in Pleuroparenchymal Fibroelastosis.

BACKGROUND: Lung biopsy remains the gold standard in the diagnosis of fibrotic interstitial lung disease (F-ILD), but there is a growing appreciation of the role of pathogenic gene variants in telomere and surfactant protein genes, especially in familial pulmonary fibrosis (FPF). Pleuroparenchymal fibroelastosis (PPFE) is a rare disease that can coexist with different patterns of F-ILD, including FPF. It can be progressive and often leads to respiratory failure and death. This study tested the hypothesis that genetic testing goes beyond radiological and histological findings in PPFE and other F-ILD further informing clinical decision-making for patients and affected family members by identifying pathological gene variants in telomere and surfactant protein genes. METHODS: This is a retrospective review of 70 patients with F-ILD in the setting of FPF or premature lung fibrosis. Six out of 70 patients were diagnosed with PPFE based on radiological or histological characteristics. All patients underwent telomere length evaluation in peripheral blood by Flow-FISH or genetic testing using a customized exome-based panel that included telomere and surfactant protein genes associated with lung fibrosis. RESULTS: Herein, we identified six individuals where radiographic or histopathological analyses of PPFE were linked with telomere biology disorders (TBD) or variants in surfactant protein genes. Each case involved individuals with either personal early-onset lung fibrosis or a family history of the disease. Assessments of telomere length and genetic testing offered insights beyond traditional radiological and histopathological evaluations. CONCLUSION: Detecting anomalies in TBD-related or surfactant protein genes can significantly refine the diagnosis and treatment strategies for individuals with PPFE and other F-ILD.

Impact of combined pulmonary fibrosis and emphysema on lung cancer risk and mortality in rheumatoid arthritis: A multicenter retrospective cohort study.

OBJECTIVE: Combined pulmonary fibrosis and emphysema (CPFE) is a syndrome characterized by the coexistence of emphysema and fibrotic interstitial lung disease (ILD). The aim of this study was to examine the effect of CPFE on lung cancer risk and lung cancer-related mortality in patients with rheumatoid arthritis (RA). METHODS: We conducted a multicenter retrospective cohort study of patients newly diagnosed with lung cancer at five community hospitals between June 2006 and December 2021. Patients were followed until lung cancer-related death, other-cause death, loss to follow-up, or the end of the study. We used the cumulative incidence function with Gray's test and Fine-Gray regression analysis for survival analysis. RESULTS: A total of 563 patients with biopsy-proven lung cancer were included (82 RA patients and 481 non-RA patients). The prevalence of CPFE was higher in RA patients than in non-RA patients (40.2% vs.10.0%) at lung cancer diagnosis. During follow-up, the crude incidence rate of lung cancer-related death was 0.29 and 0.10 per patient-year (PY) in RA and non-RA patients, and 0.32 and 0.07 per PY in patients with CPFE and patients without ILD or emphysema, respectively. The estimated death probability at 5 years differed between RA and non-RA patients (66% vs. 32%, p<0.001) and between patients with CPFE and patients without ILD or emphysema (71% vs. 24%, p<0.001). In addition to clinical cancer stage and no surgery within 1 month, RA and CPFE were identified as independent predictive factors for increased lung cancer-related mortality (RA: adjusted hazard ratio [HR], 2.49; 95% confidence interval [CI], 1.65-4.76; CPFE: adjusted HR 2.01; 95% CI 1.24-3.23). CONCLUSIONS: RA patients with lung cancer had a higher prevalence of CPFE and increased cancer-related mortality compared with non-RA patients. Close monitoring and optimal treatment strategies tailored to RA patients with CPFE are important to improve the poor prognosis of lung cancer.

First ever characterisation of the effects of short telomeres in a Singapore interstitial lung disease cohort.

BACKGROUND: Differences in disease behaviour and genotypes are described in Asian and Western interstitial lung disease (ILD) cohorts. Short leukocyte telomere length (LTL) correlates with poor outcomes in Western ILD cohorts but its significance in Asian populations is unknown. We aim to characterise the burden and clinical implications of short LTL in Singaporean ILD patients. METHODS: Patients diagnosed with ILD at Singapore General Hospital were prospectively recruited and compared against 36 healthy controls. The primary outcome was transplant-free survival. Genomic DNA from peripheral blood was extracted and LTL measured using quantitative polymerase chain reaction assay (qPCR). RESULTS: Amongst 165 patients, 37% had short LTL. There was a higher proportion of combined pulmonary fibrosis and emphysema (CPFE) patients with short LTL (n = 21, 34.4% vs n = 16, 15.4%; p < 0.001). Short LTL patients had reduced survival at 12-, 24- and 36-months and median survival of 24 months (p < 0.001) which remained significant following adjustment for smoking, GAP Stage and radiological UIP pattern (Hazard Ratio (HR), 2.74; 95%CI:1.46, 5.11; p = 0.002). They had increased respiratory-related mortality and acute exacerbation incidences. Despite similar baseline lung function, short LTL patients had a faster decline in absolute forced vital capacity (FVC) of -105.3 (95% CI: 151.4, -59.1) mL/year compared to -58.2 (95% CI: 82.9, -33.6) mL/year (p < 0.001) in normal LTL patients. CONCLUSION: Short LTL correlated with increased mortality and faster lung function decline in our Singaporean ILD cohort with a magnitude similar to that in Western ILD cohorts. Further research is needed to integrate LTL assessment into clinical practice.

Lung nodule malignancy classification with associated pulmonary fibrosis using 3D attention-gated convolutional network with CT scans.

BACKGROUND: Chest Computed tomography (CT) scans detect lung nodules and assess pulmonary fibrosis. While pulmonary fibrosis indicates increased lung cancer risk, current clinical practice characterizes nodule risk of malignancy based on nodule size and smoking history; little consideration is given to the fibrotic microenvironment. PURPOSE: To evaluate the effect of incorporating fibrotic microenvironment into classifying malignancy of lung nodules in chest CT images using deep learning techniques. MATERIALS AND METHODS: We developed a visualizable 3D classification model trained with in-house CT dataset for the nodule malignancy classification task. Three slightly-modified datasets were created: (1) nodule alone (microenvironment removed); (2) nodule with surrounding lung microenvironment; and (3) nodule in microenvironment with semantic fibrosis metadata. For each of the models, tenfold cross-validation was performed. Results were evaluated using quantitative measures, such as accuracy, sensitivity, specificity, and area-under-curve (AUC), as well as qualitative assessments, such as attention maps and class activation maps (CAM). RESULTS: The classification model trained with nodule alone achieved 75.61% accuracy, 50.00% sensitivity, 88.46% specificity, and 0.78 AUC; the model trained with nodule and microenvironment achieved 79.03% accuracy, 65.46% sensitivity, 85.86% specificity, and 0.84 AUC. The model trained with additional semantic fibrosis metadata achieved 80.84% accuracy, 74.67% sensitivity, 84.95% specificity, and 0.89 AUC. Our visual evaluation of attention maps and CAM suggested that both the nodules and the microenvironment contributed to the task. CONCLUSION: The nodule malignancy classification performance was found to be improving with microenvironment data. Further improvement was found when incorporating semantic fibrosis information.

Predictors of Mortality in Sarcoidosis.

Sarcoidosis is a systemic granulomatous disorder that affects individuals of all racial/ethnic origins and occurs at any time of life. Spontaneous remission is frequent and may occur in 2 of 3 patients, while the remaining cases have chronic, progressive disease, with some patients presenting with organ- and life-threatening involvements. Many reports have investigated which features may be related to poor outcomes in patients with sarcoidosis. Pulmonary hypertension and respiratory failure from pulmonary fibrosis are the most common complications associated with the cause of death in sarcoidosis. Other major causes of death include cardiac, neurologic, hepatic involvement, and hemoptysis from aspergilloma.

Fibrotic Pulmonary Sarcoidosis.

Fibrotic pulmonary sarcoidosis (fPS) affects about 20% of patients. fPS carries a significant morbidity and mortality. However, its prognosis is highly variable, depending mainly on fibrosis extent, functional impairment severity, and the development of pulmonary hypertension. Moreover, fPS outcomes are also influenced by several other complications, including acute exacerbations, and infections. fPS natural history is unknown, in particular regarding the risk of progressive self-sustaining fibrosis. The management of fPS is challenging, including anti-inflammatory treatment if granulomatous activity persists, rehabilitation, and in highly selected patients antifibrotic treatment and lung transplantation.

Lung fibrosis is uncommon in primary Sjögren's disease: A retrospective analysis of computed tomography features in 77 patients.

PURPOSE: The purpose of this study was to describe lung abnormalities observed on computed tomography (CT) in patients meeting the 2016 American College of Rheumatology/European League Against Rheumatism (EULAR) classification criteria for primary Sjögren's disease (pSD). MATERIALS AND METHODS: All patients with pSD seen between January 2009 and December 2020 in the day care centre of our National Reference Center for rare systemic autoimmune diseases, who had at least one chest CT examination available for review and for whom the cumulative EULAR Sjögren's Syndrome Disease Activity Index (cumESSDAI) could be calculated were retrospectively evaluated. CT examinations were reviewed, together with clinical symptoms and pulmonary functional results. RESULTS: Seventy-seven patients (73 women, four men) with a median age of 51 years at pSD diagnosis (age range: 17-79 years), a median follow-up time of 6 years and a median cumESSDAI of 7 were included. Sixty-six patients (86%) had anti-SSA antibodies. Thirty-three patients (33/77; 43%) had respiratory symptoms, without significant alteration in pulmonary function tests. Forty patients (40/77; 52%) had abnormal lung CT findings of whom almost half of them had no respiratory symptoms. Abnormalities on chest CT were more frequently observed in patients with anti-SSA positivity and a history of lymphoma. Air cysts (28/77; 36%) and mosaic perfusion (35/77; 35%) were the predominant abnormalities, whereas lung fibrosis was observed in five patients (5/77; 6%). CONCLUSION: More than half of patients with pSD have abnormal CT findings, mainly air cysts and mosaic perfusion, indicative of small airways disease, whereas lung fibrosis is rare, observed in less than 10% of such patients.

An Adult Case of Idiopathic Pulmonary Hemosiderosis Associated with Pulmonary Fibrosis and Emphysematous Change.

A 48-year-old woman was admitted to our hospital with acute respiratory failure. Chest computed tomography showed ground-glass opacity and patchy emphysematous lesions in both lungs. Corticosteroid therapy was effective; however, the disease worsened with the tapering of corticosteroids. Bronchoalveolar lavage revealed hemosiderin-laden macrophages, and video-assisted thoracic surgery showed diffuse interstitial fibrosis with diffuse alveolar hemorrhage (DAH). There was no evidence of vasculitis nor autoimmune diseases. This patient was diagnosed with idiopathic pulmonary hemosiderosis (IPH) that progressed to end-stage pulmonary fibrosis despite treatment. Autopsy demonstrated DAH with pulmonary fibrosis and emphysematous change, suggesting IPH-related pulmonary lesions.

Asbestos burden in lungs of mesothelioma patients with pleural plaques, lung fibrosis and/or ferruginous bodies at histology: a postmortem SEM-EDS study.

The causal attribution of asbestos-related diseases to past asbestos exposures is of crucial importance in clinical and legal contexts. Often this evaluation is made based on the history of exposure, but this method presents important limitations. To assess past asbestos exposure, pleural plaques (PP), lung fibrosis and histological evidence of ferruginous bodies (FB) can be used in combination with anamnestic data. However, such markers have never been associated with a threshold value of inhaled asbestos. With this study we attempted to shed light on the dose-response relationship of PP, lung fibrosis and FBs, investigating if their prevalence in exposed individuals who died from malignant mesothelioma (MM) is related to the concentration of asbestos in lungs assessed using scanning electron microscopy equipped with energy dispersive spectroscopy. Moreover, we estimated the values of asbestos concentration in lungs associated with PP, lung fibrosis and FB. Lung fibrosis showed a significant positive relationship with asbestos lung content, whereas PP and FB did not. We identified, for the first time, critical lung concentrations of asbestos related to the presence of PP, lung fibrosis and FB at histology (respectively, 19 800, 26 400 and 27 400 fibers per gram of dry weight), that were all well-below the background levels of asbestos identified in our laboratory. Such data suggest that PP, lung fibrosis and FB at histology should be used with caution in the causal attribution of MM to past asbestos exposures, while evaluation of amphibole lung content using analytical electron microscopy should be preferred.

Desquamative Interstitial Pneumonia with Progressive Pulmonary Fibrosis.

A 70-year-old man who smoked was referred to our hospital because of progressive cough and dyspnea. Radiologic images showed ground-glass attenuation predominantly in the lower lung lobes. A surgical lung biopsy was performed, and a diagnosis of desquamative interstitial pneumonia (DIP) was made. The patient's symptoms improved with smoking cessation and steroid treatment, but the ground-glass attenuation did not completely resolve. At 10 years after the diagnosis, the fibrotic lesions deteriorated and treatment with nintedanib was subsequently initiated. Careful observation is needed in patients with DIP whose lung involvement does not completely improve with initial treatment.

Combined Pulmonary Fibrosis and Emphysema: A Narrative Review.

Combined pulmonary fibrosis and emphysema (CPFE) syndrome refers to co-occurrence of two disease processes in the lung that can be difficult to diagnose but is associated with high morbidity and mortality burden. Diagnosis of CPFE is challenging because the two diseases can counterbalance respective impairments resulting in deceivingly normal-appearing chest radiography and spirometry in a dyspneic patient. Although an international committee published the terminology and definitions of CPFE in 2022, consensus on exact diagnostic criteria and optimal management strategy is yet to be determined. Herein, we provide a narrative review summarizing the literature on CPFE from 1990 to 2022, including historical background, epidemiology, pathogenesis, clinical features, imaging and pulmonary function findings, diagnosis, prognosis, complications, and treatment. Although CPFE was initially conceived as a variant presentation of idiopathic pulmonary fibrosis, it has been recognized to occur in patients with a wide variety of interstitial lung diseases, including connective tissue disease-associated interstitial lung diseases, and hypersensitivity pneumonitis. The affected patients have a heightened risk for pulmonary hypertension and lung cancer. Clinicians need to recognize the characteristic presenting features of CPFE along with prognostic implications of this entity.

Diagnosis of interstitial lung disease (ILD) secondary to systemic sclerosis (SSc) and rheumatoid arthritis (RA) and identification of 'progressive pulmonary fibrosis' using chest CT: a narrative review.

Interstitial lung disease (ILD) is a frequent manifestation of connective tissue diseases (CTDs), with incidence and prevalence variously assessed in the literature but reported in up to 30% of patients, with higher frequency in rheumatoid arthritis (RA) and systemic sclerosis (SSc). Recent years have seen a growing interest in the pulmonary manifestations of ILD-CTDs, mainly due to the widening of the use of anti-fibrotic drugs initially introduced exclusively for IPF, and radiologists play a key role because the lung biopsy is very rarely used in these patients where the morphological assessment is essentially left to imaging and especially HRCT. In this narrative review we will discuss, from the radiologist's point of view, the most recent findings in the field of ILD secondary to SSc and RA, with a special focus about the progression of disease and in particular about the 'progressive pulmonary fibrosis' (PPF) phenotype, and we will try to address two main issues: How to predict a possible evolution and therefore a worse prognosis when diagnosing a new case of ILD-CTDs and how to assess the progression of an already diagnosed ILD-CTDs.

Outcomes Following Lung Transplant for COVID-19-Related Complications in the US.

Importance: The COVID-19 pandemic led to the use of lung transplant as a lifesaving therapy for patients with irreversible lung injury. Limited information is currently available regarding the outcomes associated with this treatment modality. Objective: To describe the outcomes following lung transplant for COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis. Design, Setting, and Participants: In this cohort study, lung transplant recipient and donor characteristics and outcomes following lung transplant for COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis were extracted from the US United Network for Organ Sharing database from March 2020 to August 2022 with a median (IQR) follow-up period of 186 (64-359) days in the acute respiratory distress syndrome group and 181 (40-350) days in the pulmonary fibrosis group. Overall survival was calculated using the Kaplan-Meier method. Cox proportional regression models were used to examine the association of certain variables with overall survival. Exposures: Lung transplant following COVID-19-related acute respiratory distress syndrome or pulmonary fibrosis. Main Outcomes and Measures: Overall survival and graft failure rates. Results: Among 385 included patients undergoing lung transplant, 195 had COVID-19-related acute respiratory distress syndrome (142 male [72.8%]; median [IQR] age, 46 [38-54] years; median [IQR] allocation score, 88.3 [80.5-91.1]) and 190 had COVID-19-related pulmonary fibrosis (150 male [78.9%]; median [IQR] age, 54 [45-62]; median [IQR] allocation score, 78.5 [47.7-88.3]). There were 16 instances of acute rejection (8.7%) in the acute respiratory distress syndrome group and 15 (8.6%) in the pulmonary fibrosis group. The 1-, 6-, and 12- month overall survival rates were 0.99 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.91-0.98), and 0.88 (95% CI, 0.80-0.94) for the acute respiratory distress syndrome cohort and 0.96 (95% CI, 0.92-0.98), 0.92 (95% CI, 0.86-0.96), and 0.84 (95% CI, 0.74-0.90) for the pulmonary fibrosis cohort. Freedom from graft failure rates were 0.98 (95% CI, 0.96-0.99), 0.95 (95% CI, 0.90-0.97), and 0.88 (95% CI, 0.79-0.93) in the 1-, 6-, and 12-month follow-up periods in the acute respiratory distress cohort and 0.96 (95% CI, 0.92-0.98), 0.93 (95% CI, 0.87-0.96), and 0.85 (95% CI, 0.74-0.91) in the pulmonary fibrosis cohort, respectively. Receiving a graft from a donor with a heavy and prolonged history of smoking was associated with worse overall survival in the acute respiratory distress syndrome cohort, whereas the characteristics associated with worse overall survival in the pulmonary fibrosis cohort included female recipient, male donor, and high recipient body mass index. Conclusions and Relevance: In this study, outcomes following lung transplant were similar in patients with irreversible respiratory failure due to COVID-19 and those with other pretransplant etiologies.

Combined Pulmonary Fibrosis and Emphysema: When Scylla and Charybdis Ally.

Combined pulmonary fibrosis and emphysema (CPFE) is a recently recognized syndrome that, as its name indicates, involves the existence of both interstitial lung fibrosis and emphysema in one individual, and is often accompanied by pulmonary hypertension. This debilitating, progressive condition is most often encountered in males with an extensive smoking history, and is presented by dyspnea, preserved lung volumes, and contrastingly impaired gas exchange capacity. The diagnosis of the disease is based on computed tomography imaging, demonstrating the coexistence of emphysema and interstitial fibrosis in the lungs, which might be of various types and extents, in different areas of the lung and several relative positions to each other. CPFE bears high mortality and to date, specific and efficient treatment options do not exist. In this review, we will summarize current knowledge about the clinical attributes and manifestations of CPFE. Moreover, we will focus on pathophysiological and pathohistological lung phenomena and suspected etiological factors of this disease. Finally, since there is a paucity of preclinical research performed for this particular lung pathology, we will review existing animal studies and provide suggestions for the development of additional in vivo models of CPFE syndrome.

A case of idiopathic multicentric Castleman disease with pulmonary hyalinizing granuloma-like multiple pulmonary nodules.

A 41-year-old man presented with chronic cough and chest pain. Laboratory tests revealed anemia, inflammation, hypoalbuminemia, polyclonal hypergammaglobulinemia, and elevated interleukin-6 levels. Computed tomography revealed diffuse bilateral pulmonary nodules and multicentric lymphadenopathy. Histopathology of the pulmonary nodule resembled pulmonary hyalinizing granuloma (PHG), whereas lymph node histopathology was consistent with idiopathic multicentric Castleman disease (iMCD). The patient was diagnosed with iMCD involving PHG-like pulmonary nodules. Little is known about the association between these two diseases, and the present case provides insights regarding the relationship between PHG and iMCD.

Autoantibodies against PIP4K2B and AKT3 Are Associated with Skin and Lung Fibrosis in Patients with Systemic Sclerosis.

Systemic sclerosis (SSc) is a rare autoimmune systemic disease that leads to decreased survival and quality of life due to fibrosis, inflammation, and vascular damage in the skin and/or vital organs. Early diagnosis is crucial for clinical benefit in SSc patients. Our study aimed to identify autoantibodies in the plasma of SSc patients that are associated with fibrosis in SSc. Initially, we performed a proteome-wide screening on sample pools from SSc patients by untargeted autoantibody screening on a planar antigen array (including 42,000 antigens representing 18,000 unique proteins). The selection was complemented with proteins reported in the literature in the context of SSc. A targeted antigen bead array was then generated with protein fragments representing the selected proteins and used to screen 55 SSc plasma samples and 52 matched controls. We found eleven autoantibodies with a higher prevalence in SSc patients than in controls, eight of which bound to proteins associated with fibrosis. Combining these autoantibodies in a panel could lead to the subgrouping of SSc patients with fibrosis. Anti-Phosphatidylinositol-5-phosphate 4-kinase type 2 beta (PIP4K2B)- and anti-AKT Serine/Threonine Kinase 3 (AKT3)-antibodies should be further explored to confirm their association with skin and lung fibrosis in SSc patients.

Critical Role of LMCD1 in Promoting Profibrotic Characteristics of Lung Myofibroblasts in Experimental and Scleroderma-Associated Lung Fibrosis.

OBJECTIVE: Interstitial lung disease (ILD) is a serious complication and leading cause of mortality in patients with systemic sclerosis (SSc). In this study, we explored the role of LIM and cysteine-rich domains protein 1 (LMCD1) as a novel factor in the pathogenesis of SSc-related ILD (SSc-ILD). METHODS: The expression and effects of LMCD1 were studied in lung tissue samples and fibroblasts from SSc-ILD patients and control subjects as well as in lung tissue samples from animal models. RESULTS: LMCD1 was consistently elevated in lung tissue samples and in fibroblasts isolated from SSc-ILD patients as compared to controls. Additionally, LMCD1 was found to be highly expressed in the lung in the fibroblast-specific protein (FSP)-driven, constitutively active transforming growth factor ß receptor type I (TGFßR1) transgenic mouse model of ILD and the bleomycin-induced mouse model of ILD. In lung fibroblasts from SSc-ILD patients, LMCD1 is an essential factor for the TGFß-induced generation of type I collagen, fibronectin, and α-smooth muscle actin (α-SMA). Depletion of LMCD1 by small interfering RNA reduced the expression of extracellular matrix proteins and lowered transcriptional activity and expression of α-SMA, as well as decreased the proliferation and contractile activity of SSc-ILD lung fibroblasts. In dense fibrotic areas of affected lung tissue, lung LMCD1 colocalized with α-SMA. In cultured scleroderma lung fibroblasts, LMCD1 colocalized and interacted with serum response factor which mediates LMCD1-induced contractile activity of lung fibroblasts. CONCLUSION: Our study identifies LMCD1 as a profibrotic molecule contributing to the activation of myofibroblasts and the persistent fibroproliferation observed in SSc-ILD. Thus, LMCD1 may be a potential novel therapeutic target for patients with SSc-ILD.

Deletion of sphingosine kinase 2 attenuates cigarette smoke-mediated chronic obstructive pulmonary disease-like symptoms by reducing lung inflammation.

Cigarette smoke (CS) is the leading cause of chronic obstructive pulmonary disease (COPD), which is characterized by chronic bronchial inflammation and emphysema. Growing evidence supports the hypothesis that dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR) is critically involved in the pathogenesis of CS-mediated COPD. However, the underlying mechanism remains unclear. Here, we report that supressed CFTR expression is strongly associated with abnormal phospholipid metabolism and increased pulmonary inflammation. In a CS-exposed mouse model with COPD-like symptoms, we found that pulmonary expression of sphingosine kinase 2 (SphK2) and sphingosine-1-phosphate (S1P) secretion were significantly upregulated. Therefore, we constructed a SphK2 gene knockout (SphK2-/-) mouse. After CS exposure for six months, histological lung section staining showed disorganized alveolar structure, increased pulmonary fibrosis, and emphysema-like symptoms in wild-type (WT) mice, which were less pronounced in SphK2-/- mice. Further, SphK2 deficiency also decreased CS-induced pulmonary inflammation, which was reflected by a remarkable reduction in pulmonary infiltration of CD45+CD11b+ neutrophils subpopulation and low levels of IL-6 and IL-33 in bronchial alveolar lavage fluid. However, treatment with S1P receptor agonist suppressed CFTR expression and increased Nf-κB-p65 expression and its nuclear translocation in CS-exposed SphK2-/-mice, which also aggravated small airways fibrosis and pulmonary inflammation. In contrast, inhibition of S1P signaling with the S1P receptor analogue FTY720 rescued CFTR expression, suppressed Nf-κB-p65 expression and nuclear translocation, and alleviated pulmonary fibrosis and inflammation after CS exposure. Our results demonstrate that SphK2-mediated S1P production plays a crucial role in the pathogenesis of CS-induced COPD-like disease by impairing CFTR activity and promoting pulmonary inflammation and fibrosis.