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Smoking is a leading risk factor of chronic obstructive pulmonary disease (COPD), that is characterized by chronic lung inflammation, tissue remodeling and emphysema. Although inflammation is critical to COPD pathogenesis, the cellular and molecular basis underlying smoking-induced lung inflammation and pathology remains unclear. Using murine smoke models and single-cell RNA-sequencing, we show that smoking establishes a self-amplifying inflammatory loop characterized by an influx of molecularly heterogeneous neutrophil subsets and excessive recruitment of monocyte-derived alveolar macrophages (MoAM). In contrast to tissue-resident AM, MoAM are absent in homeostasis and characterized by a pro-inflammatory gene signature. Moreover, MoAM represent 46% of AM in emphysematous mice and express markers causally linked to emphysema. We also demonstrate the presence of pro-inflammatory and tissue remodeling associated MoAM orthologs in humans that are significantly increased in emphysematous COPD patients. Inhibition of the IRAK4 kinase depletes a rare inflammatory neutrophil subset, diminishes MoAM recruitment, and alleviates inflammation in the lung of cigarette smoke-exposed mice. This study extends our understanding of the molecular signaling circuits and cellular dynamics in smoking-induced lung inflammation and pathology, highlights the functional consequence of monocyte and neutrophil recruitment, identifies MoAM as key drivers of the inflammatory process, and supports their contribution to pathological tissue remodeling., Competing Interests: Author FG was employed by company C. H. Boehringer Sohn AG & Co. KG. CW, CWa, YS, GL, CT, FH, DK, BS, DD, CV, and PB were employed by Boehringer Ingelheim Pharma GmbH & Co. KG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Wohnhaas, Baßler, Watson, Shen, Leparc, Tilp, Heinemann, Kind, Stierstorfer, Delić, Brunner, Gantner, Schultze, Viollet and Baum.)

Introduction: We previously showed that attenuated glucocorticoid receptor (GR) function in mice (GR dim/dim ) aggravates systemic hypotension and impairs organ function during endotoxic shock. Hemorrhagic shock (HS) causes impaired organ perfusion, which leads to tissue hypoxia and inflammation with risk of organ failure. Lung co-morbidities like chronic obstructive pulmonary disease (COPD) can aggravate tissue hypoxia via alveolar hypoxia. The most common cause for COPD is cigarette smoke (CS) exposure. Therefore, we hypothesized that affecting GR function in mice (GR dim/dim ) and pre-traumatic CS exposure would further impair hemodynamic stability and organ function after HS., Methods: After 3 weeks of CS exposure, anesthetized and mechanically ventilated GR dim/dim and GR +/+ mice underwent pressure-controlled HS for 1h via blood withdrawal (mean arterial pressure (MAP) 35mmHg), followed by 4h of resuscitation with re-transfusion of shed blood, colloid fluid infusion and, if necessary, continuous intravenous norepinephrine. Acid-base status and organ function were assessed together with metabolic pathways. Blood and organs were collected at the end of the experiment for analysis of cytokines, corticosterone level, and mitochondrial respiratory capacity. Data is presented as median and interquartile range., Results: Nor CS exposure neither attenuated GR function affected survival. Non-CS GR dim/dim mice had a higher need of norepinephrine to keep target hemodynamics compared to GR +/+ mice. In contrast, after CS exposure norepinephrine need did not differ significantly between GR dim/dim and GR +/+ mice. Non-CS GR dim/dim mice presented with a lower pH and increased blood lactate levels compared to GR +/+ mice, but not CS exposed mice. Also, higher plasma concentrations of some pro-inflammatory cytokines were observed in non-CS GR dim/dim compared to GR +/+ mice, but not in the CS group. With regards to metabolic measurements, CS exposure led to an increased lipolysis in GR dim/dim compared to GR +/+ mice, but not in non-CS exposed animals., Conclusion: Whether less metabolic acidosis or increased lipolysis is the reason or the consequence for the trend towards lower catecholamine need in CS exposed GR dim/dim mice warrants further investigation., Competing Interests: Authors CT, MK, and JB are employed by Boehringer Ingelheim Pharma GmbH & Co KG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wepler, Preuss, Tilp, Keck, Blender, Wachter, Merz, Vogt, Kress, Gröger, Hoffmann, Fink, Calzia, Burret, Radermacher, Tuckermann and Vettorazzi.)