High antinuclear antibody titer is associated with increased mortality risk in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a diagnosis of exclusion, requiring that potential etiologies of interstitial lung disease be ruled out. Antinuclear antibody (ANA) testing is commonly performed in individuals with IPF, but the clinical significance of ANA positivity remains uncertain. A retrospective search identified 161 patients diagnosed with IPF between May 2010 and January 2021. Data on ANA titers at the time of diagnosis were available in all cases. Mean age of the patients was 66.4 ± 9.6 years; 70.8% were male. ANA titers were high (≥ 1:160) in 25.4% of the cohort. Baseline characteristics were comparable between those with high and low ANA titers. During follow-up (median 28 months), 93 patients (57%) died. On Cox proportional-hazards analysis with lung transplantation entered as a competing risk and adjusting for potential confounders (age, sex, and baseline forced vital capacity and diffusing lung capacity for carbon monoxide), ANA ≥ 1:160, as a dichotomized variable, was significantly associated with case-specific mortality (HR 2.25, 95% CI 1.14-4.42, P = 0.02) and older age (for each 10-year increment, HR 1.55, 95% CI 1.07-2.25, P = 0.02). High ANA titers appear to be associated with increased mortality in IPF. This finding emphasizes the potential prognostic value of ANA testing. Further studies are needed to validate these findings and explore their implications for patient management.

Single-cell transcriptomics reveals CD8+ T cell structure and developmental trajectories in idiopathic pulmonary fibrosis.

Immune cells in the human lung are associated with idiopathic pulmonary fibrosis. However, the contribution of different immune cell subpopulations to the pathogenesis of pulmonary fibrosis remains unclear. We used single-cell RNA sequencing data to investigate the transcriptional profiles of immune cells in the lungs of 5 IPF patients and 3 subjects with non-fibrotic lungs. In an identifiable population of immune cells, we found increased percentage of CD8+ T cells in the T cell subpopulation in IPF. Monocle analyzed the dynamic immune status and cell transformation of CD8+ T cells, as well as the cytotoxicity and exhausted status of CD8+ T cell subpopulations at different stages. Among CD8+ T cells, we found differences in metabolic pathways in IPF and Ctrl, including lipid, amino acid and carbohydrate metabolic. By analyzing the metabolites of CD8+ T cells, we found that different populations of CD8+ T cells in IPF have unique metabolic characteristics, but they also have multiple identical up-regulated or down-regulated metabolites. In IPF, signaling pathways associated with fibrosis were enriched in CD8+ T cells, suggesting that CD8+ T cells may have an important contribution to fibrosis. Finally, we analyzed the interactions between CD8+ T cells and other cells. Together, these studies highlight key features of CD8+ T cells in the pathogenesis of IPF and help to develop effective therapeutic targets.

Immune cells crosstalk Pathways, and metabolic alterations in Idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) presents a challenging progression characterized by lung tissue scarring and abnormal extracellular matrix deposition. This review examines the influence of immune responses, emphasizing their complex role in initiating and perpetuating fibrosis. It highlights how metabolic pathways modulate immune cell function during IPF. Immune cell modulation holds promise in managing pulmonary fibrosis (PF). Inhibiting neutrophil recruitment and monitoring mast cell levels offer insights into PF progression. Low-dose IL-2 therapy and regulation of fibroblast recruitment present potential therapeutic avenues, while the role of innate lymphoid cells (ILC2s) in allergic lung inflammation sheds light on disease mechanisms. The review focuses on metabolic reprogramming's role in shaping immune cell function during IPF progression. While some immune cells use glycolysis for pro-inflammatory responses, others favor fatty acid oxidation for regulatory functions. Targeting specialized pro-resolving lipid mediators (SPMs) presents significant potential for managing fibrotic disorders. Additionally, it highlights the pivotal role of amino acid metabolism in synthesizing serine and glycine as crucial regulators of collagen production and exploring the interconnectedness of lipid metabolism, mitochondrial dysfunction, and adipokines in driving fibrotic processes. Moreover, the review discusses the impact of metabolic disorders such as obesity and diabetes on lung fibrosis. Advocating for a holistic approach, it emphasizes the importance of considering this interplay between immune cell function and metabolic pathways in developing effective and personalized treatments for IPF.

Novel kinase 1 regulates CD8+T cells as a potential therapeutic mechanism for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic and progressively worsening lung disease that poses a significant threat to patient prognosis, with a mortality rate exceeding that of some common malignancies. Effective methods for early diagnosis and treatment remain for this condition are elusive. In our study, we used the GEO database to access second-generation sequencing data and associated clinical information from IPF patients. By utilizing bioinformatics techniques, we identified crucial disease-related genes and their biological functions, and characterized their expression patterns. Furthermore, we mapped out the immune landscape of IPF, which revealed potential roles for novel kinase 1 and CD8+T cells in disease progression and outcome. These findings can aid the development of new strategies for the clinical diagnosis and treatment of IPF.

IL20Rb aggravates pulmonary fibrosis through enhancing bone marrow derived profibrotic macrophage activation.

Idiopathic pulmonary fibrosis (IPF) is one of the most fatal chronic interstitial lung diseases with unknown pathogenesis, current treatments cannot truly reverse the progression of the disease. Pulmonary macrophages, especially bone marrow derived pro-fibrotic macrophages, secrete multiple kinds of profibrotic mediators (SPP1, CD206, CD163, IL-10, CCL18…), thus further promote myofibroblast activation and fibrosis procession. IL20Rb is a cell-surface receptor that belongs to IL-20 family. The role of IL20Rb in macrophage activation and pulmonary fibrosis remains unclear. In this study, we established a bleomycin-induced pulmonary fibrosis model, used IL4/13-inducing THP1 cells to induce profibrotic macrophage (M2-like phenotype) polarization models. We found that IL20Rb is upregulated in the progression of pulmonary fibrosis, and its absence can alleviate the progression of pulmonary fibrosis. In addition, we demonstrated that IL20Rb promote the activation of bone marrow derived profibrotic macrophages by regulating the Jak2/Stat3 and Pi3k/Akt signaling pathways. In terms of therapeutic strategy, we used IL20Rb neutralizing antibodies for animal administration, which was found to alleviate the progression of IPF. Our results suggest that IL20Rb plays a profibrotic role by promoting profibrotic macrophage polarization, and IL20Rb may become a potential therapeutic target for IPF. Neutralizing antibodies against IL20Rb may become a potential drug for the clinical treatment of IPF.

Tacrolimus alleviates pulmonary fibrosis progression through inhibiting the activation and interaction of ILC2 and monocytes.

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous group of lung diseases with different etiologies and characterized by progressive fibrosis. This disease usually causes pulmonary structural remodeling and decreased pulmonary function. The median survival of IPF patients is 2-5 years. Predominantly accumulation of type II innate immune cells accelerates fibrosis progression by secreting multiple pro-fibrotic cytokines. Group 2 innate lymphoid cells (ILC2) and monocytes/macrophages play key roles in innate immunity and aggravate the formation of pro-fibrotic environment. As a potent immunosuppressant, tacrolimus has shown efficacy in alleviating the progression of pulmonary fibrosis. In this study, we found that tacrolimus is capable of suppressing ILC2 activation, monocyte differentiation and the interaction of these two cells. This effect further reduced activation of monocyte-derived macrophages (Mo-M), thus resulting in a decline of myofibroblast activation and collagen deposition. The combination of tacrolimus and nintedanib was more effective than either drug alone. This study will reveal the specific process of tacrolimus alleviating pulmonary fibrosis by regulating type II immunity, and explore the potential feasibility of tacrolimus combined with nintedanib in the treatment of pulmonary fibrosis. This project will provide new ideas for clinical optimization of anti-pulmonary fibrosis drug strategies.

[Research progress of PD-L1 in inflammatory lung diseases].

Programmed death-ligand 1 (PD-L1) is important in maintaining central and peripheral immune tolerance in normal tissues, mediating tumor immune escape and keeping the balance between anti- and pro-inflammatory responses. Inflammation plays an important role in inflammatory lung diseases. This article reviews the research progress and potential clinical value of PD-L1 in inflammatory lung diseases, including acute lung injury, chronic obstructive pulmonary disease, asthma and idiopathic pulmonary fibrosis.

Anti-mutated citrullinated vimentin antibodies are increased in IPF patients.

INTRO: An increased prevalence of serum anti-MCV antibody is observed in the serum of patients with idiopathic pulmonary fibrosis (IPF) but the clinical relevance of these antibodies is unknown. METHODS: Patients from our center with a diagnosis of IPF according to the 2018 ATS/ERS/JRS/ALAT guidelines and at least one anti-MCV assay available were selected. All patients were part of the prospective cohort European IPF registry and selected between 03/2010 and 03/2018. We constituted two groups of patients according to the anti-MCV status at baseline to compare their characteristics at baseline and the evolution of lung function, survival and/or transplantation status. RESULTS: Anti-MCV data were available for 101 patients, of whom 86 had complete clinical data available. Twenty-nine (34 %) patients had a positive anti-MCV assay (MCV+), at a low level in most patients (29 UI/mL [IQR 25-40]), and 57 (66 %) patients a negative assay (MCV-). MCV+ patients were 20 men and 9 women, with a median age of 73 years [IQR 67-78]. MCV- patients were 49 men and 8 women with a median age of 72 years [IQR 64-77]. Sixty-two (75 %) patients were ex-smokers and 5 (6 %) were active smokers. Median cumulative tobacco smoke exposure was 22.5 (15.0-38.6) and was similar in both groups. Lung function test results and HRCT pattern distribution was similar in both groups at baseline. The median duration of follow-up was 3.5 years [IQR 2.1-5.0]. Lung function decline was similar in both groups. During the study period, 31 (36 %) patients died or have been transplanted with no difference in transplant-free survival status between the two groups. CONCLUSION: Low level anti-MCV autoimmunity was prevalent in IPF patients.

Tacrolimus ameliorates bleomycin-induced pulmonary fibrosis by inhibiting M2 macrophage polarization via JAK2/STAT3 signaling.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease of unknown cause and characterized by excessive proliferation of fibroblasts and the irregular remodeling of extracellular matrix (ECM), which ultimately cause the severe distortion of the alveolar architecture. The median survival of IPF patients is 2-5 years. IPF patients are predominantly infiltrated by M2 macrophages during the course of disease development and progression. Predominantly accumulation of M2 macrophages accelerates fibrosis progression by secreting multiple cytokines that promote fibroblast to myofibroblast transition. In the process of M2 macrophage polarization, JAK2/STAT3 signaling plays a key role, thus, targeting activated macrophages to inhibit the pro-fibrotic phenotype is considered as an approach to the potential treatment of IPF. Tacrolimus is a macrolide antibiotic that as a specific inhibitor of T-lymphocyte function and has been used widely as an immunosuppressant in human organ transplantation. In this study we explored the potential effect and mechanism of tacrolimus on pulmonary fibrosis in vivo and vitro. Here, we found that tacrolimus is capable of suppressing M2 macrophages polarization by inhibiting pro-fibrotic factors secreted by M2 macrophages. This effect further alleviates M2-induced myofibroblast activation, thus resulting in a decline of collagen deposition, pro-fibrotic cytokines secretion, recovering of lung function, ultimately relieving the progression of fibrosis in vivo. Mechanistically, we found that tacrolimus can inhibit the activation of JAK2/STAT3 signaling by targeting JAK2. Our findings indicate a potential anti-fibrotic effect of tacrolimus by regulating macrophage polarization and might be meaningful in clinical settings.

Acute exacerbation in antineutrophil cytoplasmic antibody-associated interstitial lung disease: Clinical features and risk factors.

BACKGROUND: Acute exacerbation (AE) is a life-threatening clinical event that occurs during the clinical course of idiopathic pulmonary fibrosis (IPF). Several studies have reported that AE also occurs in interstitial lung disease (ILD) other than IPF. However, the incidence, clinical features, risk factors for AE, and major causes of death in antineutrophil cytoplasmic antibody (ANCA)-associated ILD (ANCA-ILD) patients have not been well established. METHODS: We retrospectively reviewed the data of 54 ANCA-ILD patients and 304 IPF patients. We investigated the frequency of AE, post-AE prognoses, risk factors for AE, and major causes of death in ANCA-ILD patients. We also compared the data of ANCA-ILD with that of IPF. RESULTS: Fourteen (25.9%) ANCA-ILD patients and 84 (27.6%) IPF patients developed AE. The median survival times (MSTs) after AE in ANCA-ILD and IPF patients were 35.5 and 60 days, respectively (p = 0.588, log-rank test). In a multivariate analysis, the percentage of predicted forced vital capacity (%FVC) [O.R. 0.750 (95% CI 0.570, 0.986), p < 0.01] and serum C-reactive protein (CRP) [O.R. 2.202 (95% CI 1.037, 4.674), p < 0.01] were independent risk factors for AE. AE was the most frequent cause of death in ANCA-ILD and IPF patients. CONCLUSION: ANCA-ILD patients could develop AE, and the frequency of AE in ANCA-ILD is similar to that in IPF. AE is the most frequent cause of death in ANCA-ILD patients. A low %FVC and a high serum CRP level were independent predictive factors for AE in ANCA-ILD. The prognosis after AE in ANCA-ILD was poor, as it was in IPF.

B Cells Are Not Involved in the Regulation of Adenoviral TGF-ß1- or Bleomycin-Induced Lung Fibrosis in Mice.

Idiopathic pulmonary fibrosis (IPF) is an irreversible, age-related diffuse parenchymal lung disease of poorly defined etiology. Many patients with IPF demonstrate distinctive lymphocytic interstitial infiltrations within remodeled lung tissue with uncertain pathogenetic relevance. Histopathological examination of explant lung tissue of patients with IPF revealed accentuated lymphoplasmacellular accumulations in close vicinity to, or even infiltrating, remodeled lung tissue. Similarly, we found significant accumulations of B cells interfused with T cells within remodeled lung tissue in two murine models of adenoviral TGF-ß1 or bleomycin (BLM)-induced lung fibrosis. Such B cell accumulations coincided with significantly increased lung collagen deposition, lung histopathology, and worsened lung function in wild-type (WT) mice. Surprisingly, B cell-deficient µMT knockout mice exhibited similar lung tissue remodeling and worsened lung function upon either AdTGF-ß1 or BLM as for WT mice. Comparative transcriptomic profiling of sorted B cells collected from lungs of AdTGF-ß1- and BLM-exposed WT mice identified a large set of commonly regulated genes, but with significant enrichment observed for Gene Ontology terms apparently not related to lung fibrogenesis. Collectively, although we observed B cell accumulations in lungs of IPF patients as well as two experimental models of lung fibrosis, comparative profiling of characteristic features of lung fibrosis between WT and B cell-deficient mice did not support a major involvement of B cells in lung fibrogenesis in mice.

Fibrotic lung disease inhibits immune responses to staphylococcal pneumonia via impaired neutrophil and macrophage function.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by collagen deposition within the lung interstitium. Bacterial infection is associated with increased morbidity and more rapid mortality in IPF patient populations, and pathogens such as methicillin-resistant Staphylococcus aureus (MRSA) are commonly isolated from the lungs of hospitalized patients with IPF. Despite this, the effects of fibrotic lung injury on critical immune responses to infection remain unknown. In the present study, we show that, like humans with IPF, fibrotic mice infected with MRSA exhibit increased morbidity and mortality compared with uninfected fibrotic mice. We determine that fibrosis conferred a defect in MRSA clearance compared with nonfibrotic mice, resulting from blunted innate immune responses. We show that fibrosis inhibited neutrophil intracellular killing of MRSA through impaired neutrophil elastase release and oxidative radical production. Additionally, we demonstrate that lung macrophages from fibrotic mice have impaired phagocytosis of MRSA. Our study describes potentially novel impairments of antimicrobial responses upon pulmonary fibrosis development, and our findings suggest a possible mechanism for why patients with IPF are at greater risk of morbidity and mortality related to infection.

B7H3 expression and significance in idiopathic pulmonary fibrosis.

The clinical significance of B7H3 (CD276) and its cleavage product soluble B7H3 (sB7H3) in idiopathic pulmonary fibrosis (IPF) is unknown. Mounting evidence suggests the potential utility of peripheral blood myeloid cell enumeration to predict disease outcome and indicate active lung disease. Here we hypothesized that sB7H3 is involved in regulation of circulating myeloid cells in pulmonary fibrosis. In support of this possibility, both plasma sB7H3 and B7H3+ cells were elevated in IPF patient blood samples, which correlated negatively with lung function. To analyze its function, the effects of sB7H3 on naïve or bleomycin-treated mice were examined. The results revealed that sB7H3 injection induced an influx of myeloid-derived suppressor cells (MDSCs) and Ccl2 expression in lung tissue of naïve mice, accompanied by enhanced overall inflammation. Additionally, sB7H3 caused accumulation of MDSCs in bone marrow with increased expression of inflammatory cytokines. Notably, in vitro assays revealed chemotaxis of MDSCs to sB7H3, which was dependent on TLT-2 (TREML2), a putative receptor for sB7H3. Thus, increased circulating sB7H3 and/or B7H3+ cells in IPF patient blood samples correlated with lung function decline and potential immunosuppressive status. The correlation of sB7H3 with deterioration of lung function might be due to its ability to enhance inflammation and recruitment of MDSCs into the lung and their expansion in the bone marrow, and thus potentially contribute to IPF exacerbation. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

CD247, a Potential T Cell-Derived Disease Severity and Prognostic Biomarker in Patients With Idiopathic Pulmonary Fibrosis.

Background: Idiopathic pulmonary fibrosis (IPF) has high mortality worldwide. The CD247 molecule (CD247, as known as T-cell surface glycoprotein CD3 zeta chain) has been reported as a susceptibility locus in systemic sclerosis, but its correlation with IPF remains unclear. Methods: Datasets were acquired by researching the Gene Expression Omnibus (GEO). CD247 was identified as the hub gene associated with percent predicted diffusion capacity of the lung for carbon monoxide (Dlco% predicted) and prognosis according to Pearson correlation, logistic regression, and survival analysis. Results: CD247 is significantly downregulated in patients with IPF compared with controls in both blood and lung tissue samples. Moreover, CD247 is significantly positively associated with Dlco% predicted in blood and lung tissue samples. Patients with low-expression CD247 had shorter transplant-free survival (TFS) time and more composite end-point events (CEP, death, or decline in FVC >10% over a 6-month period) compared with patients with high-expression CD247 (blood). Moreover, in the follow-up 1st, 3rd, 6th, and 12th months, low expression of CD247 was still the risk factor of CEP in the GSE93606 dataset (blood). Thirteen genes were found to interact with CD247 according to the protein-protein interaction network, and the 14 genes including CD247 were associated with the functions of T cells and natural killer (NK) cells such as PD-L1 expression and PD-1 checkpoint pathway and NK cell-mediated cytotoxicity. Furthermore, we also found that a low expression of CD247 might be associated with a lower activity of TIL (tumor-infiltrating lymphocytes), checkpoint, and cytolytic activity and a higher activity of macrophages and neutrophils. Conclusion: These results imply that CD247 may be a potential T cell-derived disease severity and prognostic biomarker for IPF.

Interrelation Between Fibroblasts and T Cells in Fibrosing Interstitial Lung Diseases.

Interstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by varying degrees of inflammation and fibrosis of the pulmonary interstitium. The interrelations between multiple immune cells and stromal cells participate in the pathogenesis of ILDs. While fibroblasts contribute to the development of ILDs through secreting extracellular matrix and proinflammatory cytokines upon activation, T cells are major mediators of adaptive immunity, as well as inflammation and autoimmune tissue destruction in the lung of ILDs patients. Fibroblasts play important roles in modulating T cell recruitment, differentiation and function and conversely, T cells can balance fibrotic sequelae with protective immunity in the lung. A more precise understanding of the interrelation between fibroblasts and T cells will enable a better future therapeutic design by targeting this interrelationship. Here we highlight recent work on the interactions between fibroblasts and T cells in ILDs, and consider the implications of these interactions in the future development of therapies for ILDs.

Deleterious Role of Th9 Cells in Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease of unknown etiology. Immune disorders play an important role in IPF pathogenesis. Here, we show that Th9 cells differentiate and activate in the lung tissue of patients with IPF and bleomycin (BLM)-induced lung fibrosis mice. Moreover, we found that Th9 cells promote pulmonary fibrosis in two ways. On the one hand, Th9 cells promote fibroblast differentiation, activation, and collagen secretion by secreting IL-9. On the other hand, they promote differentiation of Th0 cells into Th2 cells by secreting IL-4. Th9 cells and Th2 cells can promote each other, accelerating the Th1/Th2 imbalance and eventually forming a positive feedback of pulmonary fibrosis. In addition, we found that neutralizing IL-9 in both preventive and therapeutic settings ameliorates bleomycin-induced pulmonary fibrosis. Furthermore, we identified several critical signaling pathways involved in the effect of neutralizing IL-9 on pulmonary fibrosis by proteomics study. From an immunological perspective, we elucidated the novel role and underlying mechanism of Th9 cells in pulmonary fibrosis. Our study suggested that Th9-based immunotherapy may be employed as a treatment strategy for IPF.

The Role of Epithelial Damage in the Pulmonary Immune Response.

Pulmonary epithelial cells are widely considered to be the first line of defence in the lung and are responsible for coordinating the innate immune response to injury and subsequent repair. Consequently, epithelial cells communicate with multiple cell types including immune cells and fibroblasts to promote acute inflammation and normal wound healing in response to damage. However, aberrant epithelial cell death and damage are hallmarks of pulmonary disease, with necrotic cell death and cellular senescence contributing to disease pathogenesis in numerous respiratory diseases such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and coronavirus disease (COVID)-19. In this review, we summarise the literature that demonstrates that epithelial damage plays a pivotal role in the dysregulation of the immune response leading to tissue destruction and abnormal remodelling in several chronic diseases. Specifically, we highlight the role of epithelial-derived damage-associated molecular patterns (DAMPs) and senescence in shaping the immune response and assess their contribution to inflammatory and fibrotic signalling pathways in the lung.

The Crucial Role of NLRP3 Inflammasome in Viral Infection-Associated Fibrosing Interstitial Lung Diseases.

Idiopathic pulmonary fibrosis (IPF), one of the most common fibrosing interstitial lung diseases (ILD), is a chronic-age-related respiratory disease that rises from repeated micro-injury of the alveolar epithelium. Environmental influences, intrinsic factors, genetic and epigenetic risk factors that lead to chronic inflammation might be implicated in the development of IPF. The exact triggers that initiate the fibrotic response in IPF remain enigmatic, but there is now increasing evidence supporting the role of chronic exposure of viral infection. During viral infection, activation of the NLRP3 inflammasome by integrating multiple cellular and molecular signaling implicates robust inflammation, fibroblast proliferation, activation of myofibroblast, matrix deposition, and aberrant epithelial-mesenchymal function. Overall, the crosstalk of the NLRP3 inflammasome and viruses can activate immune responses and inflammasome-associated molecules in the development, progression, and exacerbation of IPF.

Essential role of IL-23 in the development of acute exacerbation of pulmonary fibrosis.

Acute exacerbation of idiopathic pulmonary fibrosis has a poor prognosis associated with neutrophilic inflammation. Interleukin-23 is a proinflammatory cytokine involved in neutrophilic inflammation. However, little is known about its role in acute exacerbation of pulmonary fibrosis. This study was performed to determine the role of interleukin-23 in acute exacerbation of pulmonary fibrosis. For assessment of acute exacerbation of pulmonary fibrosis, mice were intratracheally administered bleomycin followed by lipopolysaccharide. Inflammatory cells, cytokine levels, and morphological morphometry of the lungs were analyzed. Cytokine levels were measured in the bronchoalveolar lavage fluid of idiopathic pulmonary fibrosis patients with or without acute exacerbation. Interleukin-23, -17A, and -22 levels were increased in the airway of mice with acute exacerbation of pulmonary fibrosis. Interleukin-23p19-deficient mice with acute exacerbation of pulmonary fibrosis had markedly reduced airway inflammation and fibrosis associated with decreased levels of interleukin-17A and -22 compared with wild-type mice. Treatment with an anti-interleukin-23 antibody attenuated airway inflammation and fibrosis and reduced interleukin-17A and -22 levels in mice with acute exacerbation of pulmonary fibrosis. T-helper type 17 cells were the predominant source of interleukin-17A in mice with acute exacerbation of pulmonary fibrosis. Interleukin-23 levels in bronchoalveolar lavage fluid tended to be higher in idiopathic pulmonary fibrosis patients with than without acute exacerbation. The data presented here suggest that interleukin-23 is essential for the development of acute exacerbation of pulmonary fibrosis and that blockade of interleukin-23 may be a new therapeutic strategy for acute exacerbation of pulmonary fibrosis.