Disease-specific transcriptional programs govern airway goblet cell metaplasia.

Hypersecretion of airway mucus caused by goblet cell metaplasia is a characteristic of chronic pulmonary inflammatory diseases including asthma, cystic fibrosis (CF), and chronic obstructive pulmonary disease (COPD). Goblet cells originate from airway progenitor club cells. However, the molecular mechanisms and features of goblet cell metaplasia in lung disease are poorly understood. Herein, public single-cell RNA sequencing datasets of human lungs were reanalyzed to explore the transitional phase as club cells differentiate into goblet cells in asthma, CF, and COPD. We found that changes in club and goblet cells during pathogenesis and cellular transition were associated with signalling pathways related to immune response, oxidative stress, and apoptosis. Moreover, other key drivers of goblet cell specification appeared to be pathologically specific, with interleukin (IL)-13 and hypoxia inducible factor 1 (HIF-1)-induced genetic changes in asthma, cystic fibrosis transmembrane conductance regulator (CFTR) mutation being present in CF, and interactions with CD8+ T cells, mitophagy, and mitochondria-induced apoptosis in COPD. In conclusion, this study revealed the similarities and differences in goblet cell metaplasia in asthma, CF, and COPD at the transcriptome level, thereby providing insights into possible novel therapeutic approaches for these diseases.

Fatty acids metabolism in ozone-induced pulmonary inflammatory injury: Evidence, mechanism and prevention.

Ozone (O3) is a major air pollutant that directly threatens the respiratory system, lung fatty acid metabolism disorder is an important molecular event in pulmonary inflammatory diseases. Liver kinase B1 (LKB1) and nucleotide-binding domain leucine-rich repeat-containing protein 3 (NLRP3) inflammasome not only regulate inflammation, but also have close relationship with fatty acid metabolism. However, the role and mechanism of LKB1 and NLRP3 inflammasome in lung fatty acid metabolism, which may contribute to ozone-induced lung inflammation, remain unclear, and effective strategy for preventing O3-induced pulmonary inflammatory injury is lacking. To explore these, mice were exposed to 1.00 ppm O3 (3 h/d, 5 days), and pulmonary inflammation was determined by airway hyperresponsiveness, histopathological examination, total cells and cytokines in bronchoalveolar lavage fluid (BALF). Targeted fatty acids metabolomics was used to detect medium and long fatty acid in lung tissue. Then, using LKB1-overexpressing adenovirus and NLRP3 knockout (NLRP3-/-) mice to explore the mechanism of O3-induced lung fatty acid metabolism disorder. Results demonstrated that O3 exposure caused pulmonary inflammatory injury and lung medium and long chain fatty acids metabolism disorder, especially decreased dihomo-γ-linolenic acid (DGLA). Meanwhile, LKB1 expression was decreased, and NLRP3 inflammasome was activated in lung of mice after O3 exposure. Additionally, LKB1 overexpression alleviated O3-induced lung inflammation and inhibited the activation of NLRP3 inflammasome. And we found that pulmonary fatty acid metabolism disorder was ameliorated of NLRP3 -/- mice compared with those in wide type mice after O3 exposure. Furthermore, administrating DGLA intratracheally prior to O3 exposure significantly attenuated O3-induced pulmonary inflammatory injury. Taken together, these findings suggest that fatty acids metabolism disorder is involved in O3-induced pulmonary inflammation, which is regulated by LKB1-mediated NLRP3 pathway, DGLA supplement could be a useful preventive strategy to ameliorate ozone-associated lung inflammatory injury.

Cell Cross-Talk in Alveolar Microenvironment: From Lung Injury to Fibrosis.

Alveoli are complex microenvironments composed of various cell types, including epithelial, fibroblast, endothelial, and immune cells, which work together to maintain a delicate balance in the lung environment, ensuring proper growth, development, and an effective response to lung injuries. However, prolonged inflammation or aging can disrupt normal interactions among these cells, leading to impaired repair processes and a substantial decline in lung function. Therefore, it is essential to understand the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. We explored the key mechanisms underlying the interactions among the major cell types within the alveolar microenvironment. These interactions occur through the secretion of signaling factors and play crucial roles in the response to injury, repair mechanisms, and the development of fibrosis in the lungs. Specifically, we focused on the regulation of alveolar type 2 cells by fibroblasts, endothelial cells, and macrophages. In addition, we explored the diverse phenotypes of fibroblasts at different stages of life and in response to lung injury, highlighting their impact on matrix production and immune functions. Furthermore, we summarize the various phenotypes of macrophages in lung injury and fibrosis as well as their intricate interplay with other cell types. This interplay can either contribute to the restoration of immune homeostasis in the alveoli or impede the repair process. Through a comprehensive exploration of these cell interactions, we aim to reveal new insights into the molecular mechanisms that drive lung injury toward fibrosis and identify potential targets for therapeutic intervention.

PM2.5 induces a senescent state in mouse AT2 cells.

PM2.5 is known to induce lung injury, but its toxic effects on lung regenerative machinery and the underlying mechanisms remain unknown. In this study, primary mouse alveolar type 2 (AT2) cells, considered stem cells in the gas-exchange barrier, were sorted using fluorescence-activated cell sorting. By developing microfluidic technology with constricted microchannels, we observed that both passage time and impedance opacities of mouse AT2 cells were reduced after PM2.5, indicating that PM2.5 induced a more deformable mechanical property and a higher membrane permeability. In vitro organoid cultures of primary mouse AT2 cells indicated that PM2.5 is able to impair the proliferative potential and self-renewal capacity of AT2 cells but does not affect AT1 differentiation. Furthermore, cell senescence biomarkers, p53 and γ-H2A.X at protein levels, P16ink4a and P21 at mRNA levels were increased in primary mouse AT2 cells after PM2.5 stimulations as shown by immunofluorescent staining and quantitative PCR analysis. Using several advanced single-cell technologies, this study sheds light on new mechanisms of the cytotoxic effects of atmospheric fine particulate matter on lung stem cell behavior.

Short-term PM2.5 exposure induces transient lung injury and repair.

Exposure to fine atmospheric particulate matter (PM) is known to induce lung inflammation and injury; however, the way in which sophisticated endogenous lung repair and regenerative programs respond to this exposure remains unknown. In this study, we established a whole-body mouse exposure model to mimic real scenarios. Exposure to fine PM (PM with an aerodynamic diameter ≤ 2.5 µm [PM2.5]; mean 1.05 mg/m3) for 1-month elicited inflammatory infiltration and epithelial alterations in the lung, which were resolved 6 months after cessation of exposure. Immune cells that responded to PM2.5 exposure mainly included macrophages and neutrophils. During PM2.5 exposure, alveolar epithelial type 2 cells initiated rapid repair of alveolar epithelial mucosa through proliferation. However, the reparative capacity of airway progenitor cells (club cells) was impaired, which may have been related to the oxidative production of neutrophils or macrophages, as suggested in organoid co-cultures. These data suggested that the pulmonary toxic effects of short-term exposure to fine atmospheric PM at a certain dosage could be overcome through tissue reparative mechanisms.

Multi-omics blood atlas reveals unique features of immune and platelet responses to SARS-CoV-2 Omicron breakthrough infection.

Although host responses to the ancestral SARS-CoV-2 strain are well described, those to the new Omicron variants are less resolved. We profiled the clinical phenomes, transcriptomes, proteomes, metabolomes, and immune repertoires of >1,000 blood cell or plasma specimens from SARS-CoV-2 Omicron patients. Using in-depth integrated multi-omics, we dissected the host response dynamics during multiple disease phases to reveal the molecular and cellular landscapes in the blood. Specifically, we detected enhanced interferon-mediated antiviral signatures of platelets in Omicron-infected patients, and platelets preferentially formed widespread aggregates with leukocytes to modulate immune cell functions. In addition, patients who were re-tested positive for viral RNA showed marked reductions in B cell receptor clones, antibody generation, and neutralizing capacity against Omicron. Finally, we developed a machine learning model that accurately predicted the probability of re-positivity in Omicron patients. Our study may inspire a paradigm shift in studying systemic diseases and emerging public health concerns.

Plasma metabolomic characterization of SARS-CoV-2 Omicron infection.

Omicron variants of SARS-CoV-2 have spread rapidly worldwide; however, most infected patients have mild or no symptoms. This study aimed to understand the host response to Omicron infections by performing metabolomic profiling of plasma. We observed that Omicron infections triggered an inflammatory response and innate immune, and adaptive immunity was suppressed, including reduced T-cell response and immunoglobulin antibody production. Similar to the original SARS-CoV-2 strain circulating in 2019, the host developed an anti-inflammatory response and accelerated energy metabolism in response to Omicron infection. However, differential regulation of macrophage polarization and reduced neutrophil function has been observed in Omicron infections. Interferon-induced antiviral immunity was not as strong in Omicron infections as in the original SARS-CoV-2 infections. The host response to Omicron infections increased antioxidant capacity and liver detoxification more than in the original strain. Hence, these findings suggest that Omicron infections cause weaker inflammatory alterations and immune responses than the original SARS-CoV-2 strain.

Nitric oxide hinders club cell proliferation through Gdpd2 during allergic airway inflammation.

Excessive nitric oxide (NO) is often observed in the airways of patients with severe asthma. Here, we show that the NO donor diethylamine NONOate impairs the proliferative capacity of mouse club cells and induces club cell apoptosis, cell cycle arrest, and alterations in lipid metabolism. Our data suggest that NO inhibits club cell proliferation via upregulation of Gdpd2 (glycerophosphodiester phosphodiesterase domain containing 2). During ovalbumin (OVA) challenge, apoptotic club cells are observed, but surviving club cells continue to proliferate. OVA exposure induces Gdpd2 expression; Gdpd2 knockout promotes the proliferation of club cells but inhibits goblet cell differentiation. Elimination of airway NO was found to inhibit goblet cell differentiation from club cells during OVA challenge. Our data reveal that excessive NO might be related to airway epithelial damage in severe asthma and suggest that blockade of the NO-Gdpd2 pathway may be beneficial for airway epithelial restoration.

Multiomic characterisation of the long-term sequelae of SARS survivors: a clinical observational study.

Background: We aimed to characterise the long-term health outcomes of survivors of severe acute respiratory syndrome (SARS) and determine their recovery status and possible immunological basis. Methods: We performed a clinical observational study on 14 health workers who survived SARS coronavirus infection between Apr 20, 2003 and Jun 6, 2003 in Haihe Hospital (Tianjin, China). Eighteen years after discharge, SARS survivors were interviewed using questionnaires on symptoms and quality of life, and received physical examination, laboratory tests, pulmonary function tests, arterial blood gas analysis, and chest imaging. Plasma samples were collected for metabolomic, proteomic, and single-cell transcriptomic analyses. The health outcomes were compared 18 and 12 years after discharge. Control individuals were also health workers from the same hospital but did not infect with SARS coronavirus. Findings: Fatigue was the most common symptom in SARS survivors 18 years after discharge, with osteoporosis and necrosis of the femoral head being the main sequelae. The respiratory function and hip function scores of the SARS survivors were significantly lower than those of the controls. Physical and social functioning at 18 years was improved compared to that after 12 years but still worse than the controls. Emotional and mental health were fully recovered. Lung lesions on CT scans remained consistent at 18 years, especially in the right upper lobe and left lower lobe lesions. Plasma multiomics analysis indicated an abnormal metabolism of amino acids and lipids, promoted host defense immune responses to bacteria and external stimuli, B-cell activation, and enhanced cytotoxicity of CD8+ T cells but impaired antigen presentation capacity of CD4+ T cells. Interpretation: Although health outcomes continued to improve, our study suggested that SARS survivors still suffered from physical fatigue, osteoporosis, and necrosis of the femoral head 18 years after discharge, possibly related to plasma metabolic disorders and immunological alterations. Funding: This study was funded by the Tianjin Haihe Hospital Science and Technology Fund (HHYY-202012) and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-063B, TJYXZDXK-067C).

Niche-Dependent Regulation of Lkb1 in the Proliferation of Lung Epithelial Progenitor Cells.

Lung homeostasis and regeneration depend on lung epithelial progenitor cells. Lkb1 (Liver Kinase B1) has known roles in the differentiation of airway epithelial cells during embryonic development. However, the effects of Lkb1 in adult lung epithelial progenitor cell regeneration and its mechanisms of action have not been determined. In this study, we investigated the mechanism by which Lkb1 regulates lung epithelial progenitor cell regeneration. Organoid culture showed that loss of Lkb1 significantly reduced the proliferation of club cells and alveolar type 2 (AT2) cells in vitro. In the absence of Lkb1, there is a slower recovery rate of the damaged airway epithelium in naphthalene-induced airway epithelial injury and impaired expression of surfactant protein C during bleomycin-induced alveolar epithelial damage. Moreover, the expression of autophagy-related genes was reduced in club cells and increased in AT2 cells, but the expression of Claudin-18 was obviously reduced in AT2 cells after Lkb1 knockdown. On the whole, our findings indicated that Lkb1 may promote the proliferation of lung epithelial progenitor cells via a niche-dependent pathway and is required for the repair of the damaged lung epithelium.

DJ-1 governs airway progenitor cell/eosinophil interactions to promote allergic inflammation.

BACKGROUND: DJ-1 is an antioxidant protein known to regulate mast cell-mediated allergic response, but its role in airway eosinophilic interactions and allergic inflammation is not known. OBJECTIVE: The aim of this study was to investigate the role of DJ-1 in airway eosinophilic inflammation in vitro and in vivo. METHODS: Ovalbumin-induced airway allergic inflammation was established in mice. ELISA was adopted to analyze DJ-1 and cytokine levels in mouse bronchoalveolar lavage fluid. Transcriptional profiling of mouse lung tissues was conducted by single-cell RNA-sequencing technology. The role of DJ-1 in the differentiation of airway progenitor cells into goblet cells was examined by organoid cultures, immunofluorescence staining, quantitative PCR, and cell transplantation in normal, DJ-1 knockout (KO), or conditional DJ-1 KO mice. RESULTS: This study observed that DJ-1 was increased in the lung tissues of ovalbumin-sensitized and challenged mice. DJ-1 KO mice exhibited reduced airway eosinophil infiltration and goblet cell differentiation. Mechanistically, we discovered that eosinophil-club cell interactions are reduced in the absence of DJ-1. Organoid cultures indicated that eosinophils impair the proliferative potential of club cells. Intratracheal transplantation of DJ-1-deficient eosinophils suppresses airway goblet cell differentiation. Loss of DJ-1 inhibits the metabolism of arachidonic acid into cysteinyl leukotrienes in eosinophils while these secreted metabolites promote airway goblet cell fate in organoid cultures and in vivo. CONCLUSIONS: DJ-1-mediated interactions between airway epithelial progenitor cells and immune cells are essential in controlling airway goblet cell metaplasia and eosinophilia. Blockade of the DJ-1 pathway is protective against airway allergic inflammation.

Glutamine Metabolism Is Required for Alveolar Regeneration during Lung Injury.

(1) Background: Abnormal repair after alveolar epithelial injury drives the progression of idiopathic pulmonary fibrosis (IPF). The maintenance of epithelial integrity is based on the self-renewal and differentiation of alveolar type 2 (AT2) cells, which require sufficient energy. However, the role of glutamine metabolism in the maintenance of the alveolar epithelium remains unclear. In this study, we investigated the role of glutamine metabolism in AT2 cells of patients with IPF and in mice with bleomycin-induced fibrosis. (2) Methods: Single-cell RNA sequencing (scRNA-seq), transcriptome, and metabolomics analyses were conducted to investigate the changes in the glutamine metabolic pathway during pulmonary fibrosis. Metabolic inhibitors were used to stimulate AT2 cells to block glutamine metabolism. Regeneration of AT2 cells was detected using bleomycin-induced mouse lung fibrosis and organoid models. (3) Results: Single-cell analysis showed that the expression levels of catalytic enzymes responsible for glutamine catabolism were downregulated (p < 0.001) in AT2 cells of patients with IPF, suggesting the accumulation of unusable glutamine. Combined analysis of the transcriptome (p < 0.05) and metabolome (p < 0.001) revealed similar changes in glutamine metabolism in bleomycin-induced pulmonary fibrosis in mice. Mechanistically, inhibition of the key enzymes involved in glucose metabolism, glutaminase-1 (GLS1) and glutamic-pyruvate transaminase-2 (GPT2) leads to reduced proliferation (p < 0.01) and differentiation (p < 0.01) of AT2 cells. (4) Conclusions: Glutamine metabolism is required for alveolar epithelial regeneration during lung injury.

Plasma proteomic and metabolomic characterization of COVID-19 survivors 6 months after discharge.

Coronavirus disease 2019 (COVID-19) has gained prominence as a global pandemic. Studies have suggested that systemic alterations persist in a considerable proportion of COVID-19 patients after hospital discharge. We used proteomic and metabolomic approaches to analyze plasma samples obtained from 30 healthy subjects and 54 COVID-19 survivors 6 months after discharge from the hospital, including 30 non-severe and 24 severe patients. Through this analysis, we identified 1019 proteins and 1091 metabolites. The differentially expressed proteins and metabolites were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Among the patients evaluated, 41% of COVID-19 survivors reported at least one clinical symptom and 26.5% showed lung imaging abnormalities at 6 months after discharge. Plasma proteomics and metabolomics analysis showed that COVID-19 survivors differed from healthy control subjects in terms of the extracellular matrix, immune response, and hemostasis pathways. COVID-19 survivors also exhibited abnormal lipid metabolism, disordered immune response, and changes in pulmonary fibrosis-related proteins. COVID-19 survivors show persistent proteomic and metabolomic abnormalities 6 months after discharge from the hospital. Hence, the recovery period for COVID-19 survivors may be longer.

SARS-CoV-2 Infection and Lung Regeneration.

The lung is the primary site of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced immunopathology whereby the virus enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2). Sophisticated regeneration and repair programs exist in the lungs to replenish injured cell populations. However, known resident stem/progenitor cells have been demonstrated to express ACE2, raising a substantial concern regarding the long-term consequences of impaired lung regeneration after SARS-CoV-2 infection. Moreover, clinical treatments may also affect lung repair from antiviral drug candidates to mechanical ventilation. In this review, we highlight how SARS-CoV-2 disrupts a program that governs lung homeostasis. We also summarize the current efforts of targeted therapy and supportive treatments for COVID-19 patients. In addition, we discuss the pros and cons of cell therapy with mesenchymal stem cells or resident lung epithelial stem/progenitor cells in preventing post-acute sequelae of COVID-19. We propose that, in addition to symptomatic treatments being developed and applied in the clinic, targeting lung regeneration is also essential to restore lung homeostasis in COVID-19 patients.

Organoid technology and lung injury mouse models evaluating effects of hydroxychloroquine on lung epithelial regeneration.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) damages lung epithelial stem/progenitor cells. Ideal anti-SARS-CoV-2 drug candidates should be screened to prevent secondary injury to the lungs. Here, we propose that in vitro three-dimensional organoid and lung injury repair mouse models are powerful models for the screening antiviral drugs. Lung epithelial progenitor cells, including airway club cells and alveolar type 2 (AT2) cells, were co-cultured with supportive fibroblast cells in transwell inserts. The organoid model was used to evaluate the possible effects of hydroxychloroquine, which is administered as a symptomatic therapy to the coronavirus disease 2019 (COVID-19) patients, on the function of mouse lung stem/progenitor cells. Hydroxychloroquine was observed to promote the self-renewal of club cells and differentiation of ciliated and goblet cells in vitro. Additionally, it inhibited the self-renewal ability of AT2 cells in vitro. Naphthalene- or bleomycin-induced lung injury repair mouse models were used to investigate the in vivo effects of hydroxychloroquine on the regeneration of club and AT2 cells, respectively. The naphthalene model indicated that the proliferative ability and differentiation potential of club cells were unaffected in the presence of hydroxychloroquine. The bleomycin model suggested that hydroxychloroquine had a limited effect on the proliferation and differentiation abilities of AT2 cells. These findings suggest that hydroxychloroquine has limited effects on the regenerative ability of epithelial stem/progenitor cells. Thus, stem/progenitor cell-derived organoid technology and lung epithelial injury repair mouse models provide a powerful platform for drug screening, which could possibly help end the pandemic.

Distinct Symptoms and Underlying Comorbidities with Latitude and Longitude in COVID-19: A Systematic Review and Meta-Analysis.

The coronavirus disease 2019 (COVID-19) pandemic is straining global health resources, and the prevalence of severe disease appears to vary across countries. In accordance with PRISMA guidelines, we performed a systematic review and meta-analysis of clinical features and underlying medical conditions of COVID-19. Eighty-seven studies, involving 1,434,931 COVID-19 patients from the Americas, Asia, Europe, and Oceania, were included. Geographically, the rate of severity was highest in Asia (95% confidence interval (CI) 0.23‒0.30). The rates of comorbidities of COVID-19 patients in the Americas were significantly higher than those in Asia. Most Asian patients had fever (95%CI 0.70‒0.81), and most Oceanian patients had cough (95%CI 0.68‒0.70) as their prevalent symptom. Dyspnea was common in the Americas (95%CI 0.33‒0.64), Europe (95%CI 0.29‒0.64), and high latitude regions (95%CI 0.53‒0.82). European patients exhibited significantly high rates of loss of smell and taste (95%CI 0.60-0.97). In low-latitude regions, cancer (95%CI 14.50‒4.89) had the strongest correlation with illness severity. Comorbid diseases and clinical manifestations of severe COVID-19 patients vary substantially between latitudes and longitudes. Region-specific care should be considered to treat and improve the prognosis of COVID-19 patients.

Cellular metabolic basis of altered immunity in the lungs of patients with COVID-19.

Metabolic pathways drive cellular behavior. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes lung tissue damage directly by targeting cells or indirectly by producing inflammatory cytokines. However, whether functional alterations are related to metabolic changes in lung cells after SARS-CoV-2 infection remains unknown. Here, we analyzed the lung single-nucleus RNA-sequencing (snRNA-seq) data of several deceased COVID-19 patients and focused on changes in transcripts associated with cellular metabolism. We observed upregulated glycolysis and oxidative phosphorylation in alveolar type 2 progenitor cells, which may block alveolar epithelial differentiation and surfactant secretion. Elevated inositol phosphate metabolism in airway progenitor cells may promote neutrophil infiltration and damage the lung barrier. Further, multiple metabolic alterations in the airway goblet cells are associated with impaired muco-ciliary clearance. Increased glycolysis, oxidative phosphorylation, and inositol phosphate metabolism not only enhance macrophage activation but also contribute to SARS-CoV-2 induced lung injury. The cytotoxicity of natural killer cells and CD8+ T cells may be enhanced by glycerolipid and inositol phosphate metabolism. Glycolytic activation in fibroblasts is related to myofibroblast differentiation and fibrogenesis. Glycolysis, oxidative phosphorylation, and glutathione metabolism may also boost the aging, apoptosis and proliferation of vascular smooth muscle cells, resulting in pulmonary arterial hypertension. In conclusion, this preliminary study revealed a possible cellular metabolic basis for the altered innate immunity, adaptive immunity, and niche cell function in the lung after SARS-CoV-2 infection. Therefore, patients with COVID-19 may benefit from therapeutic strategies targeting cellular metabolism in future.

Serum levels of laminin and von Willebrand factor in COVID-19 survivors 6 months after discharge.

OBJECTIVES: The aim of this study was to evaluate the clinical characteristics, pulmonary diffusion function, chest computed tomography (CT), and serum lung cell damage indicators of coronavirus disease 2019 (COVID-19) survivors 6 months after discharge. METHODS: Data of COVID-19 survivors discharged from hospital between January 21, 2020 and January 11, 2021 and healthy controls were collected. Serum levels of surfactant protein D (SP-D)1, the receptor for advanced glycation end products (RAGE)2, laminin, and von Willebrand factor (vWF) were measured in the healthy controls and COVID-19 survivors 6 months after discharge. The relationships between serum lung cell damage indicator levels and various parameters were explored. RESULTS: Fifty-two COVID-19 survivors (31 with non-severe disease and 21 with severe disease) and 30 controls were included. Serum levels of laminin in COVID-19 survivors 6 months after discharge were significantly higher than those in the controls. The increase was more significant in elderly and female patients. Serum levels of RAGE and vWF were not statistically different from those of the controls. However, 6 months after discharge, COVID-19 survivors with abnormal chest CT and those in the severe group had higher vWF levels. CONCLUSIONS: COVID-19 patients had abnormal lung injury indicators 6 months after discharge. The recovery time after infection is currently unknown, and long-term observation is required.

LKB1 deficiency upregulates RELM-α to drive airway goblet cell metaplasia.

Targeting airway goblet cell metaplasia is a novel strategy that can potentially reduce the chronic obstructive pulmonary disease (COPD) symptoms. Tumor suppressor liver kinase B1 (LKB1) is an important regulator of the proliferation and differentiation of stem/progenitor cells. In this study, we report that LKB1 expression was downregulated in the lungs of patients with COPD and in those of cigarette smoke-exposed mice. Nkx2.1Cre; Lkb1f/f mice with conditional loss of Lkb1 in mouse lung epithelium displayed airway mucus hypersecretion and pulmonary macrophage infiltration. Single-cell transcriptomic analysis of the lung tissues from Nkx2.1Cre; Lkb1f/f mice further revealed that airway goblet cell differentiation was altered in the absence of LKB1. An organoid culture study demonstrated that Lkb1 deficiency in mouse airway (club) progenitor cells promoted the expression of FIZZ1/RELM-α, which drove airway goblet cell differentiation and pulmonary macrophage recruitment. Additionally, monocyte-derived macrophages in the lungs of Nkx2.1Cre; Lkb1f/f mice exhibited an alternatively activated M2 phenotype, while expressing RELM-α, which subsequently aggravated airway goblet cell metaplasia. Our findings suggest that the LKB1-mediated crosstalk between airway progenitor cells and macrophages regulates airway goblet cell metaplasia. Moreover, our data suggest that LKB1 agonists might serve as a potential therapeutic option to treat respiratory disorders associated with goblet cell metaplasia.