Showing papers by "Friedrich Grimminger published in 2023"

Nicotine promotes e-cigarette vapour-induced lung inflammation and structural alterations

Abstract: Background Electronic cigarette (e-cigarette) vapour is gaining popularity as an alternative to tobacco smoking and can induce acute lung injury. However, the specific role of nicotine in e-cigarette vapour and its long-term effects on the airways, lung parenchyma and vasculature remain unclear. Results In vitro exposure to nicotine-containing e-cigarette vapour extract (ECVE) or to nicotine-free e-cigarette vapour extract (NF ECVE) induced changes in gene expression of epithelial cells and pulmonary arterial smooth muscle cells (PASMCs), but ECVE in particular caused functional alterations (e.g. a decrease in human and mouse PASMC proliferation by 29.3±5.3% and 44.3±8.4%, respectively). Additionally, acute inhalation of nicotine-containing e-cigarette vapour (ECV) but not nicotine-free e-cigarette vapour (NF ECV) increased pulmonary endothelial permeability in isolated lungs. Long-term in vivo exposure of mice to ECV for 8 months significantly increased the number of inflammatory cells, in particular lymphocytes, compared to control and NF ECV in the bronchoalveolar fluid (BALF) (ECV: 853.4±150.8 cells·mL−1; control: 37.0±21.1 cells·mL−1; NF ECV: 198.6±94.9 cells·mL−1) and in lung tissue (ECV: 25.7±3.3 cells·mm−3; control: 4.8±1.1 cells·mm−3; NF ECV: 14.1±2.2 cells·mm−3). BALF cytokines were predominantly increased by ECV. Moreover, ECV caused significant changes in lung structure and function (e.g. increase in airspace by 17.5±1.4% compared to control), similar to mild tobacco smoke-induced alterations, which also could be detected in the NF ECV group, albeit to a lesser degree. In contrast, the pulmonary vasculature was not significantly affected by ECV or NF ECV. Conclusions NF ECV components induce cell type-specific effects and mild pulmonary alterations, while inclusion of nicotine induces significant endothelial damage, inflammation and parenchymal alterations. E-cigarette use, particularly with nicotine-containing vapour, is a harmful alternative to tobacco smoking. Nicotine-containing e-cigarette vapour increases pulmonary endothelial permeability, induces inflammation and causes airway and parenchymal alterations. https://bit.ly/40s24n9

Decreased plasma levels of the brain-derived neurotrophic factor correlate with right heart congestion in pulmonary arterial hypertension

Abstract: Background The brain-derived neurotrophic factor (BDNF) may promote development of pulmonary hypertension and right ventricular (RV) failure. However, BDNF plasma levels were decreased in patients with left ventricular (LV) failure. Therefore, we investigated BDNF plasma levels in pulmonary hypertension patients and the role of BDNF in mouse models of pulmonary hypertension and isolated RV failure. Methods BDNF plasma levels were correlated to pulmonary hypertension in two patient cohorts, including either post- and pre-capillary pulmonary hypertension patients (first cohort) or only pre-capillary pulmonary hypertension patients (second cohort). In the second cohort, RV dimensions and load-independent function were determined by imaging and pressure–volume catheter measurements, respectively. For induction of isolated RV pressure overload, heterozygous Bdnf knockout (Bdnf+/−) mice were subjected to pulmonary arterial banding (PAB). For induction of pulmonary hypertension, mice with inducible knockout of BDNF in smooth muscle cells (Bdnf/Smmhc knockout) were exposed to chronic hypoxia. Results Plasma BDNF levels were decreased in patients with pulmonary hypertension. Following adjustment for covariables, BDNF levels negatively correlated in both cohorts with central venous pressure. In the second cohort, BDNF levels additionally negatively correlated with RV dilatation. In animal models, BDNF downregulation attenuated RV dilatation in Bdnf+/−mice after PAB or hypoxic Bdnf/Smmhc knockout mice, although they developed pulmonary hypertension to a similar extent. Conclusions Similar to LV failure, circulating levels of BDNF were decreased in pulmonary hypertension patients, and low BDNF levels were associated with right heart congestion. Decreased BDNF levels did not worsen RV dilatation in animal models, and thus, may be the consequence, but not the cause of RV dilatation. Plasma BDNF levels are decreased in IPAH patients, and correlate with central venous pressure and RV dilatation but not heart function. Low BDNF levels in animal models attenuate RV dilatation. https://bit.ly/3e2dwTK

CEACAM6 as a Novel Therapeutic Target to Boost HO-1-mediated Antioxidant Defense in COPD.

Abstract: RATIONALE Tobacco smoking and air pollution are primary causes of chronic obstructive pulmonary disease (COPD). However, only a minority of smokers develop COPD. The mechanisms underlying the defense against nitrosative/oxidative stress in non-susceptible smokers to COPD remain largely unresolved. OBJECTIVES To investigate the defense mechanisms against nitrosative/oxidative stress that possibly prevent COPD development or progression. METHODS Four cohorts were investigated: (1) sputum samples (healthy, n=4; COPD, n=37), (2) lung tissue samples (healthy, n=13; smokers without COPD, n=10; smoker+COPD, n=17), (3) pulmonary lobectomy tissue samples (no/mild emphysema, n=6) and (4) blood samples (healthy, n=6; COPD, n=18). We screened 3-nitrotyrosine (3-NT) levels, as indication of nitrosative/oxidative stress, in human samples. We established a novel in vitro model of a cigarette smoke extract (CSE)-resistant cell line and studied 3-NT formation, antioxidant capacity, and transcriptomic profiles. Results were validated in lung tissue, isolated primary cells and an ex vivo model using adeno-associated virus-mediated gene transduction and human precision-cut lung slices (hPCLS). MEASUREMENTS AND MAIN RESULTS 3-NT levels correlate with COPD severity of patients. In CSE-resistant cells, nitrosative/oxidative stress upon CSE was attenuated, paralleled by profound upregulation of heme-oxygenase-1 (HO-1). We identified carcinoembryonic-antigen-related-cell-adhesion-molecule-6 (CEACAM6) as a negative regulator of HO-1-mediated nitrosative/oxidative stress defense in human alveolar type 2 epithelial cells (hAEC2). Consistently, inhibition of HO-1 activity in hAEC2 increased the susceptibility towards CSE-induced damage. Epithelium-specific CEACAM6 overexpression increased nitrosative/oxidative stress and cell death in hPCLS upon CSE treatment. CONCLUSIONS CEACAM6 expression determines the hAEC2 sensitivity to nitrosative/oxidative stress triggering emphysema development/progression in susceptible smokers.

Data from Spatial Density and Distribution of Tumor-Associated Macrophages Predict Survival in Non–Small Cell Lung Carcinoma

Abstract: <div>Abstract<p>The respective antitumoral and protumoral roles of M1 and M2 tumor-associated macrophages (TAM) typify the complexity of macrophage function in cancer. In lung cancer, density and topology of distinct TAM phenotypes at the tumor center (TC) versus the invasive margin (IM) are largely unknown. Here, we investigated TAM subtype density and distribution between TC and IM in human lung cancer and TAM associations with overall survival. Macrophages isolated from adjacent nontumor tissue (NM), the TC (TC-TAM), and the IM (IM-TAM) were analyzed with RNA-sequencing (RNA-seq). Lung tumor tissue microarrays from 104 patient samples were constructed. M1 and M2 TAMs were identified using multiplex immunofluorescence staining and a tumor cell-TAM proximity analysis was performed. RNA-seq identified marked differences among NM, TC-TAM, and IM-TAM. On the basis of a panel of five selected markers (CD68, IL12, CCR7, CD163, and ALOX15), M2 predominance over M1 and M2 proximity to tumor cells was observed, especially at IM. Tumor cell proximity to TAM was linked with tumor cell survival and hypoxia was associated with accumulation of M2 TAM. Notably, lower density of M1 TC-TAM and higher proximity of tumor cells to M2 IM-TAM or lower proximity to M1 IM-TAM were linked with poor survival. In addition, three novel molecules (UBXN4, MFSD12, and ACTR6) from RNA-seq served as potential prognostic markers for lung cancer, and M2 predominance and juxtaposition of M2 TAM near tumor cells were associated with poor survival. Together, our results reveal the marked heterogeneity of TAM populations in different tumor regions, with M2 TAM predominance, particularly at IM.</p>Significance:<p>This study underlines the significance of the density, spatial distribution, and gene expression of TAM phenotypes as prognostic factors for overall survival in lung cancer.</p></div>

Data from Spatial Density and Distribution of Tumor-Associated Macrophages Predict Survival in Non–Small Cell Lung Carcinoma

Abstract: <div>Abstract<p>The respective antitumoral and protumoral roles of M1 and M2 tumor-associated macrophages (TAM) typify the complexity of macrophage function in cancer. In lung cancer, density and topology of distinct TAM phenotypes at the tumor center (TC) versus the invasive margin (IM) are largely unknown. Here, we investigated TAM subtype density and distribution between TC and IM in human lung cancer and TAM associations with overall survival. Macrophages isolated from adjacent nontumor tissue (NM), the TC (TC-TAM), and the IM (IM-TAM) were analyzed with RNA-sequencing (RNA-seq). Lung tumor tissue microarrays from 104 patient samples were constructed. M1 and M2 TAMs were identified using multiplex immunofluorescence staining and a tumor cell-TAM proximity analysis was performed. RNA-seq identified marked differences among NM, TC-TAM, and IM-TAM. On the basis of a panel of five selected markers (CD68, IL12, CCR7, CD163, and ALOX15), M2 predominance over M1 and M2 proximity to tumor cells was observed, especially at IM. Tumor cell proximity to TAM was linked with tumor cell survival and hypoxia was associated with accumulation of M2 TAM. Notably, lower density of M1 TC-TAM and higher proximity of tumor cells to M2 IM-TAM or lower proximity to M1 IM-TAM were linked with poor survival. In addition, three novel molecules (UBXN4, MFSD12, and ACTR6) from RNA-seq served as potential prognostic markers for lung cancer, and M2 predominance and juxtaposition of M2 TAM near tumor cells were associated with poor survival. Together, our results reveal the marked heterogeneity of TAM populations in different tumor regions, with M2 TAM predominance, particularly at IM.</p>Significance:<p>This study underlines the significance of the density, spatial distribution, and gene expression of TAM phenotypes as prognostic factors for overall survival in lung cancer.</p></div>

The HDAC2-SP1 axis orchestrates pro-tumor macrophage polarization.

Abstract: Tumor-associated macrophages (TAMs), including anti-tumor M1-like TAMs and pro-tumor M2-like TAMs, are transcriptionally dynamic innate immune cells with diverse roles in lung cancer development. Epigenetic regulators are key in controlling macrophage fate in the heterogeneous tumor microenvironment. Here, we demonstrate that the spatial proximity of HDAC2-overexpressing M2-like TAMs to tumor cells significantly correlates with poor overall survival of lung cancer patients. Suppression of HDAC2 in TAMs altered macrophage phenotype, migration, and signaling pathways related to interleukins, chemokines, cytokines, and T cell activation. In co-culture systems of TAMs and cancer cells, suppressing HDAC2 in TAMs resulted in reduced proliferation and migration, increased apoptosis of cancer cell lines and primary lung cancer cells, and attenuated endothelial cell tube formation. HDAC2 regulated the M2-like TAM phenotype via acetylation of histone H3 and transcription factor SP1. Myeloid cell-specific deletion of Hdac2 and pharmacological inhibition of class I HDACs in four different murine lung cancer models induced the switch from M2-like to M1-like TAMs, altered infiltration of CD4+ and CD8+ T cells, and reduced tumor growth and angiogenesis. TAM-specific HDAC2 expression may provide a biomarker for lung cancer stratification and a target for developing improved therapeutic approaches.