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Acute exacerbation (AE) of idiopathic pulmonary fibrosis (IPF) is a common cause of disease acceleration in IPF and has a major impact on mortality. The role of macrophage activation in AE of IPF has never been addressed before. We evaluated BAL cell cytokine profiles and BAL differential cell counts in 71 IPF patients w/wo AE and in 20 healthy volunteers. Twelve patients suffered from AE at initial diagnosis while sixteen patients developed AE in the 24 months of follow-up. The levels of IL-1ra, CCL2, CCL17, CCL18, CCL22, TNF-α, IL-1β, CXCL1 and IL-8 spontaneously produced by BAL-cells were analysed by ELISA. In patients with AE, the percentage of BAL neutrophils was significantly increased compared to stable patients. We found an increase in the production rate of the pro-inflammatory cytokines CXCL1 and IL-8 combined with an increase in all tested M2 cytokines by BAL-cells. An increase in CCL18 levels and neutrophil counts during AE was observed in BAL cells from patients from whom serial lavages were obtained. Furthermore, high baseline levels of CCL18 production by BAL cells were significantly predictive for the development of future AE. BAL cell cytokine production levels at acute exacerbation show up-regulation of pro-inflammatory as well as anti-inflammatory/ M2 cytokines. Our data suggest that AE in IPF is not an incidental event but rather driven by cellular mechanisms including M2 macrophage activation.

Background The origin of collagen-producing cells in lung fibrosis is unclear. The involvement of embryonic signaling pathways has been acknowledged and trans-differentiation of epithelial cells is discussed critically. The work presented here investigates the role of TGFB in cytoskeleton remodeling and the expression of Epithelial-Mesenchymal-Transition markers by Alveolar Epithelial Cells Type II and tests the hypothesis if human alveolar epithelial cells are capable of trans-differentiation and production of pro-fibrotic collagen. Methods Primary human alveolar epithelial cells type II were extracted from donor tissues and stimulated with TGFβ and a TGFβ-inhibitor. Transcriptome and pathway analyses as well as validation of results on protein level were conducted. Results A TGFβ-responsive fingerprint was found and investigated for mutual interactions. Interaction modules exhibited enrichment of genes that favor actin cytoskeleton remodeling, differentiation processes and collagen metabolism. Cross-validation of the TGFβ-responsive fingerprint in an independent IPF dataset revealed overlap of genes and supported the direction of regulated genes and TGFβ-specificity. Conclusions Primary human alveolar epithelial cells type II seem undergo a TGFβ-dependent phenotypic change, exhibit differential expression of EMT markers in vitro and acquire the potential to produce collagen.

A patient with severe autoimmune pneumonitis from immune checkpoint inhibitor therapy for metastatic melanoma had improved clinical and radiographic clearance of the pneumonitis associated with treatment with inhaled vasoactive intestinal peptide.

Idiopathic pulmonary fibrosis is characterized by abundant collagen production and accumulation of alternatively activated macrophages (M2) in the lower respiratory tract. Mechanisms as to how alveolar macrophages are activated by collagen breakdown products are unknown. Alveolar macrophages were obtained by bronchoalveolar lavage from 30 patients with idiopathic pulmonary fibrosis (IPF) and 37 healthy donors (HD). Alveolar macrophages were cultured in the presence of collagen type I, III, IV and V monomers w/wo a neutralizing antibody against scavenger receptor I class A (CD204). Culture supernatants were assayed for the M2 markers CCL18, CCL2, and interleukin-1 receptor antagonist (IL-1ra) by ELISA. Furthermore, expression of phospho-Akt was measured using ELISA and expression of CD204 by RT-PCR and flow cytometry. Stimulation with collagen type I and III monomers significantly up-regulated CCL18, IL-1ra production of alveolar macrophages. Furthermore, expression of CCL2 and CD204 were up-regulated by collagen type I exposure. In addition, collagen type I stimulation increased pospho-Akt expression. Collagen type I effects were abrogated by neutralizing antiCD204 and a non-selective Phosphatidylinositide 3-kinase inhibitor (LY294002). Spontaneous CD204 expression of alveolar macrophages was significantly increased in patients with IPF. In conclusion, our findings demonstrate that monomeric collagen type I via CD204 induces phospho-Akt expression shifting alveolar macrophages to the profibrotic M2 type. Innate immune responses induced by collagen monomers might perpetuate pulmonary fibrosis.

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease with a poor prognosis. There is great effort to find predictors of outcome. Conclusive data for any serum biomarker are lacking. We have recently documented that serum CCL18 concentrations correlate with the course of pulmonary function data in patients with pulmonary fibrosis of various causes. Objectives To test the value of serum CCL18 concentrations in IPF, we included 72 patients in a prospective study. Methods IPF was defined according to the ATS/ERS criteria. Serum CCL18 concentrations were measured by a commercially available ELISA. Patients were followed for 24 months. Pulmonary function tests were performed at least every 6 months. Measurements and Main Results Baseline serum CCL18 concentrations predicted the change in TLC and FVC at the 6-month follow-up. Receiver operating characteristics (ROC) revealed a significant relation between survival and baseline CCL18 concentrations. By ROC analysis, the cutoff value with the highest diagnostic accuracy was defined as 150 ng/ml (sensitivity, 0.83; specificity, 0.77). There was a significantly higher mortality in patients with serum CCL18 concentrations above 150 ng/ml (P < 0.0001). The hazard proportional ratio adjusted for age, sex, and baseline pulmonary function data was 8.0. There was a higher incidence of disease progression in the group with high serum CCL18 concentrations. Conclusions Our data demonstrate that serum CCL18 concentrations have a predictive value in IPF and may be a useful tool in the clinical management of patients with IPF and in clinical trials.

Abstract Rationale Recently, models of macrophage activation have been revised. Macrophages stimulated with Th2 cytokines have been classified as alternatively activated. Objectives This article examines the expression and regulation of CC chemokine ligand 18 (CCL18), a marker of alternative activation, by human alveolar macrophages (AMs). Methods AM were obtained from bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis, sarcoidosis, or hypersensitivity pneumonitis (n = 69) and healthy volunteers (n = 22). Expression of CCL18 was determined by quantitative reverse transcriptase–polymerase chain reaction, in situ hybridization, flow cytometry, and immunohistochemistry, respectively. Measurements and Main Results Spontaneous CCL18 production by BAL-derived cells was markedly increased in patients with pulmonary fibrosis and correlated negatively with pulmonary function test parameters. CCL18 gene expression and protein production were up-regulated in normal AMs after Th2 cytokine stimulation and/or coculture with human lung fibroblasts. Native collagen significantly up-regulated CCL18 expression in normal AMs activated with Th2 cytokines via a mechanism mediated by β2-integrin/ scavenger receptor(s). Culture supernatants of AMs from patients with idiopathic pulmonary fibrosis increased collagen production by normal lung fibroblasts partly mediated via CCL18. Conclusions Our findings suggest that AMs from patients with pulmonary fibrosis disclose a phenotype of alternative activation and might be a part of a positive feedback loop with lung fibroblasts perpetuating fibrotic processes.

A 48-year-old patient underwent lung transplantation because of severe COVID-19, which aggravated his underlying interstitial lung disease, despite the presence of detectable SARS-CoV-2. Subsequently, the graft is re-infected early in the post-procedural phase, leading to viral persistence for more than five months. By analyzing viral evolution and effector immune response within the transplanted organ, we observe three main findings. First, virus evolution differs in the transplanted organ compared to that in the upper respiratory tract and is affected by monoclonal SARS-CoV-2-specific antibodies and molnupiravir. Second, we show the potential clinical relevance of T cell HLA restriction that may facilitate viral clearance in the upper respiratory tract compared to the ongoing viral replication in the HLA mismatch organ. Third, close monitoring and modulation of immunosuppressive and antiviral therapy enables viral clearance in a lung transplantation setting despite incomplete SARS-CoV-2 clearance prior to transplantation. Human transplantation with allogeneic donor organs results in non-matching of MHC and differential presentation of T cell antigens. Here the authors show that in a lung transplanted SARS-CoV-2 infected patient T cell responses generated from the host may not be able to recognise infected cells within the graft and this may contribute to virus persistence.

IntroductionNon-necrotising granulomas are the histological hallmark of sarcoidosis and chronic beryllium disease (CBD). Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), transbronchial lung forceps biopsy (TBLB) and endobronchial biopsy (EBB) are often used as standard methods for obtaining suitable tissue. Transbronchial lung cryobiopsy (TBLC) is a novel biopsy technique well studied in different fibrosing lung diseases; however, data on its use in sarcoidosis are scarce. This study aimed to assess whether TBLC provides additional diagnostic value compared with standard diagnostic methods in detecting non-necrotising granulomas.MethodsWe retrospectively analysed 321 patients diagnosed with sarcoidosis or CBD between 2010 and 2020 in a single tertiary care centre. Patients who underwent intrathoracic biopsy were analysed to assess the diagnostic yield, factors influencing diagnostic success, as well as complications related to each technique.ResultsIntrathoracic biopsy procedures were performed on 264 patients (EBUS-TBNA n=215, EBB n=61, TBLB n=120 and TBLC n=66). The diagnostic yields for single methods ranged from 56.3% (EBB) to 63.6% (TBLC) (p=0.7643). Combination of EBUS-TBNA with TBLC increased the diagnostic yield to 91.7%. Notably, TBLC provided a superior diagnostic yield compared with TBB in cases without radiologically detected parenchymal involvement. Complication rates were numerically higher following TBLC compared with TBLB (16.7% vs 9.2%, p=0.1561).ConclusionsThe addition of TBLC significantly enhances the diagnostic yield in the workup of sarcoidosis and CBD, particularly in cases without radiologically detected parenchymal involvement. This underscores the added value of TBLC in improving diagnostic accuracy in challenging clinical scenarios.

Abstract Rationale Previous studies suggest an important immunoregulatory role of vasoactive intestinal peptide (VIP) in experimental models of chronic noninfectious inflammation. Sarcoidosis is characterized by noncaseating epitheloid cell granulomas, where excessive tumor necrosis factor-α production by pulmonary macrophages plays a critical role in granuloma formation and disease progression, which may lead to fatal organ dysfunction. Objectives To test whether inhaled VIP has an immunoregulatory role. Sarcoid alveolitis was used as a prototype of immune-mediated chronic lung inflammation. Methods In an open clinical phase II study, we treated 20 patients with histologically proved sarcoidosis and active disease with nebulized VIP for 4 weeks. Measurements and Main Results VIP inhalation was safe, well-tolerated, and significantly reduced the production of tumor necrosis factor-α by cells isolated from bronchoalveolar lavage fluids of these patients. VIP treatment significantly increased the numbers of bronchoalveolar lavage CD4+CD127−CD25+ T cells, which showed regulatory activities on conventional effector T cells. In vitro experiments demonstrated the capacity of VIP to convert naive CD4+CD25− T cells into CD4+CD25+FoxP3+ regulatory T cells, suggesting the generation of peripheral regulatory T cells by VIP treatment. Conclusions This study is the first to show the immunoregulatory effect of VIP in humans, and supports the notion of inhaled VIP as an attractive future therapy to dampen exaggerated immune responses in lung disorders. Thus, the inhalation of neuropeptides may be developed into a new therapeutic principle for chronic inflammatory lung disorders in humans.

Abstract Rationale Extracellular ATP promotes inflammation, but its role in chronic obstructive pulmonary disease (COPD) is unknown. Objectives To analyze the expression of ATP and its functional consequences in never-smokers, asymptomatic smokers, and patients with COPD. Methods ATP was quantified in bronchoalveolar lavage fluid (BALF) of never-smokers, asymptomatic smokers, and patients with COPD of different severity. The expression of specific ATP (purinergic) receptors was measured in airway macrophages and blood neutrophils from control subjects and patients with COPD. The release of mediators by macrophages and neutrophils and neutrophil chemotaxis was assessed after ATP stimulation. Measurements and Main Results Chronic smokers had elevated ATP concentrations in BALF compared with never-smokers. Acute smoke exposure led to a further increase in endobronchial ATP concentrations. Highest ATP concentrations in BALF were present in smokers and ex-smokers with COPD. In patients with COPD, BALF ATP concentrations correlated negatively with lung function and positively with BALF neutrophil counts. ATP induced a stronger chemotaxis and a stronger elastase release in blood neutrophils from patients with COPD, as compared with control subjects. In addition, airway macrophages from patients with COPD responded with an increased secretion of proinflammatory and tissue-degrading mediators after ATP stimulation. These findings were accompanied by an up-regulation of specific purinergic receptors in blood neutrophils and airway macrophages of patients with COPD. Conclusions COPD is characterized by a strong and persistent up-regulation of extracellular ATP in the airways. Extracellular ATP appears to contribute to the pathogenesis of COPD by promoting inflammation and tissue degradation.