Bronchiole adenoma/pulmonary ciliated mucinous nodular papillary tumor: Case series and literature review.

OBJECTIVE: To analyze the clinical-pathological characteristics of 3 cases of bronchiolar adenoma/pulmonary ciliary mucinous nodular papillary tumors, and to improve the understanding of bronchiolar adenoma (BA)/ciliated muconodular papillary tumors (CMPT) (bronchiolar adenoma/ciliated muconodular papillary tumor). METHODS: Retrospective analysis was done on the clinical information, diagnosis, and treatment of 3 instances of BA/CMPT at the Second People's Hospital of Weifang City. By scanning the CNKI, Wanfang, VIP database, and Pubmed database using the English key words "bronchiolar adenoma, ciliated muconodular papillary tumor," respectively patients with comprehensive clinical data were gathered, and studies from January 2002 to August 2021 that were relevant to the patients were examined. RESULTS: A total of 35 articles and 71 instances were found, including 3 cases in our hospital, for a total of 74 cases. There were 31 males and 43 females among them, ranging in age from 18 to 84 years (average 63 years), and 15 cases had a smoking history. The majority of them were discovered by physical examination and had no clinical symptoms. The majority of the imaging revealed solid nodules with variable forms, with some ground-glass nodules displaying vacuole and bronchial inflation signs. BA/CMPT are generally gray-white, gray-brown solid nodules with obvious boundaries but no envelope with a maximum dimension of 4 to 45 mm (average 10.6 mm) on gross examination. Acinar, papillary, and lepidic formations can be seen under the microscope at high magnification; the majority of these structures are made up of tripartite epithelial components, including basal cells, mucous cells, ciliated columnar cells, and alveolar epithelial cells, demonstrating a variety of combinations. An important basis for diagnosis in immunohistochemistry is the continuous positive basal cell layer that is shown by p63, p40, and CK5/6. BRAF and epidermal growth factor receptor are the genes that are most frequently mutated. All of the patients showed no signs of metastasis or recurrence during follow-up period. CONCLUSION: BA/CMPT is a rare benign tumor of lung epithelium. Because imaging and intraoperative cryosection diagnosis are easy to be misdiagnosed as malignant, it is necessary to further improve understanding and improve immunohistochemistry and genetic examination.

Clinicopathological features and genomic analysis of bronchiolar adenoma.

BACKGROUND: Bronchiolar adenoma (BA) is a rare tumor of the bronchioles with a double-layer structure, including the basal cell layer and the superficial cell layer, and it has a good prognosis. However, the concept of a putative variant of BA has been proposed in the recent literature. METHODS: Data on 17 cases of BA were collected from our center. The clinical data, morphology, immunophenotype, and molecular changes were retrospectively analyzed. We also collected the molecular changes in BA reported in the previous literature and summarized the putative driver mutations of BA. RESULTS: Out of 17 BAs, 13 were classic cases with a double-layer structure, including 9 proximal-type and 4 distal-type BAs. Of note, we also identified 3 cases that lacked a continuous basal cell layer, including 2 cases of mixed-type BA with monolayered lesions (basal cells were undetected in some areas) and 1 case of a monolayered BA-like lesion (basal cells were completely undetected). The immunohistochemical findings of monolayer cell lesions were closer to those of minimally invasive adenocarcinoma. We also found one case in which BA transformed into invasive adenocarcinoma accompanied by mutations in the TP53, JAK2, NF1 and RB1 genes. Combined with the previous literature, the most common putative driver gene mutations in 62 BA lesions were EGFR (25/62; 41%) and BRAF (21/62; 34.4%). CONCLUSION: Typical BA has a double-layer cell structure; however, there is also a putative variant of BA, which has a monolayer cell structure and lacks the basal cell layer. Transformation from BA into invasive adenocarcinoma is unusual but can occur.

Mucin distribution in bronchiolar adenoma/ciliated muconodular papillary tumor reveals organoid differentiation simulating the normal lung.

Bronchiolar adenoma/ciliated muconodular papillary tumor is a lung neoplasm exhibiting various degrees of proximal and distal bronchiolar differentiation. Here, we evaluated distribution of MUC5AC and MUC5B in bronchiolar adenoma/ciliated muconodular papillary tumor for comparison with that seen in normal respiratory tract. In normal respiratory tract, MUC5AC was mainly distributed in large bronchi, while MUC5B was distributed in bronchi, bronchioles, and submucosal glands. In bronchiolar adenoma/ciliated muconodular papillary tumor, MUC5AC was primarily distributed in luminal cells of large airspaces, and MUC5B was distributed in luminal cells of small airspaces and mucinous glands, in addition to large airspaces, regardless of distal or proximal differentiation. In particular, MUC5B was distributed in non-mucinous club and ciliated cells in both the normal respiratory tract and bronchiolar adenoma/ciliated muconodular papillary tumor. These results indicate that MUC5AC and MUC5B distribution in bronchiolar adenoma/ciliated muconodular papillary tumor is similar to that seen in normal respiratory tract, suggestive of organoid differentiation simulating the normal lung.

The molecular and cellular mechanisms associated with the destruction of terminal bronchioles in COPD.

RATIONALE: Peripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD. METHODS: Ten explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling. RESULTS: Micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ≥500 and <1000 µm, which we have termed a "hot spot". Based on microarray gene expression profiling, the hot spot was associated with an 11-gene signature, with upregulation of pro-inflammatory genes and downregulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT, which predicts the percentage of immune cells in tissues from transcriptomic data, showed that the hot spot regions were associated with increased infiltration of CD4 and CD8 T-cell and B-cell lymphocytes. INTERPRETATION: The reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of IFNG signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in COPD.

Sustained Club Cell Injury in Mice Induces Histopathologic Features of Deployment-Related Constrictive Bronchiolitis.

Histopathologic evidence of deployment-related constrictive bronchiolitis (DRCB) has been identified in soldiers deployed to Southwest Asia. While inhalational injury to the airway epithelium is suspected, relatively little is known about the pathogenesis underlying this disabling disorder. Club cells are local progenitors critical for repairing the airway epithelium after exposure to various airborne toxins, and a prior study using an inducible transgenic murine model reported that 10 days of sustained targeted club cell injury causes constrictive bronchiolitis. To further understand the mechanisms leading to small airway fibrosis, a murine model was employed to show that sustained club cell injury elicited acute weight loss, caused increased local production of proinflammatory cytokines, and promoted accumulation of numerous myeloid cell subsets in the lung. Transition to a chronic phase was characterized by up-regulated expression of oxidative stress-associated genes, increased activation of transforming growth factor-ß, accumulation of alternatively activated macrophages, and enhanced peribronchiolar collagen deposition. Comparative histopathologic analysis demonstrated that sustained club cell injury was sufficient to induce epithelial metaplasia, airway wall thickening, peribronchiolar infiltrates, and clusters of intraluminal airway macrophages that recapitulated key abnormalities observed in DRCB. Depletion of alveolar macrophages in mice decreased activation of transforming growth factor-ß and ameliorated constrictive bronchiolitis. Collectively, these findings implicate sustained club cell injury in the development of DRCB and delineate pathways that may yield biomarkers and treatment targets for this disorder.

Role of Secretoglobin+ (club cell) NFκB/RelA-TGFß signaling in aero-allergen-induced epithelial plasticity and subepithelial myofibroblast transdifferentiation.

Repetitive aeroallergen exposure is linked to sensitization and airway remodeling through incompletely understood mechanisms. In this study, we examine the dynamic mucosal response to cat dander extract (CDE), a ubiquitous aero-allergen linked to remodeling, sensitization and asthma. We find that daily exposure of CDE in naïve C57BL/6 mice activates innate neutrophilic inflammation followed by transition to a lymphocytic response associated with waves of mucosal transforming growth factor (TGF) isoform expression. In parallel, enhanced bronchiolar Smad3 expression and accumulation of phospho-SMAD3 was observed, indicating paracrine activation of canonical TGFßR signaling. CDE exposure similarly triggered epithelial cell plasticity, associated with expression of mesenchymal regulatory factors (Snai1 and Zeb1), reduction of epithelial markers (Cdh1) and activation of the NFκB/RelA transcriptional activator. To determine whether NFκB functionally mediates CDE-induced growth factor response, mice were stimulated with CDE in the absence or presence of a selective IKK inhibitor. IKK inhibition substantially reduced the level of CDE-induced TGFß1 expression, pSMAD3 accumulation, Snai1 and Zeb1 expression. Activation of epithelial plasticity was demonstrated by flow cytometry in whole lung homogenates, where CDE induces accumulation of SMA+Epcam+ population. Club cells are important sources of cytokine and growth factor production. To determine whether Club cell innate signaling through NFκB/RelA mediated CDE induced TGFß signaling, we depleted RelA in Secretoglobin (Scgb1a1)-expressing bronchiolar cells. Immunofluorescence-optical clearing light sheet microscopy showed a punctate distribution of Scgb1a1 progenitors throughout the small airway. We found that RelA depletion in Secretoglobin+ cells results in inhibition of the mucosal TGFß response, blockade of EMT and reduced subepithelial myofibroblast expansion. We conclude that the Secretoglobin-derived bronchiolar cell is central to coordinating the innate response required for mucosal TGFß1 response, EMT and myofibroblast expansion. These data have important mechanistic implications for how aero-allergens trigger mucosal injury response and remodeling in the small airway.

Waning antibodies from inactivated SARS-CoV-2 vaccination offer protection against infection without antibody-enhanced immunopathology in rhesus macaque pneumonia models.

Inactivated coronaviruses, including severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) and Middle East respiratory syndrome coronavirus (MERS-CoV), as potential vaccines have been reported to result in enhanced respiratory diseases (ERDs) in murine and nonhuman primate (NHP) pneumonia models after virus challenge, which poses great safety concerns of antibody-dependent enhancement (ADE) for the rapid wide application of inactivated SARS-CoV-2 vaccines in humans, especially when the neutralizing antibody levels induced by vaccination or initial infection quickly wane to nonneutralizing or subneutralizing levels over the time. With passive transfer of diluted postvaccination polyclonal antibodies to mimic the waning antibody responses after vaccination, we found that in the absence of cellular immunity, passive infusion of subneutralizing or nonneutralizing anti-SARS-CoV-2 antibodies could still provide some level of protection against infection upon challenge, and no low-level antibody-enhanced infection was observed. The anti-SARS-CoV-2 IgG-infused group and control group showed similar, mild to moderate pulmonary immunopathology during the acute phase of virus infection, and no evidence of vaccine-related pulmonary immunopathology enhancement was found. Typical immunopathology included elevated MCP-1, IL-8 and IL-33 in bronchoalveolar lavage fluid; alveolar epithelial hyperplasia; and exfoliated cells and mucus in bronchioles. Our results corresponded with the recent observations that no pulmonary immunology was detected in preclinical studies of inactivated SARS-CoV-2 vaccines in either murine or NHP pneumonia models or in large clinical trials and further supported the safety of inactivated SARS-CoV-2 vaccines.

[Hypersensitivity Pneumonitis - an important differential diagnosis of infiltrative lung diseases]. / Exogen allergische Alveolitis ­ Eine wichtige Differenzialdiagnose der infiltrativen Lungenerkrankungen.

Hypersensitivity pneumonitis (HP) is an inflammatory and/or fibrotic disease of the lung parenchyma and terminal bronchioles caused by an allergic reaction to inhaled antigens. The immune response following antigen exposure results in lymphocytic inflammation as well as granuloma formation.The typical histologic pattern of HP consists of cellular interstitial pneumonia, cellular bronchiolitis, and epithelioid cell granulomas. The additional presence of fibrosis has a significant impact on the course as well as the prognosis of the disease and represents a therapeutic approach. Therefore, a classification into a non-fibrotic and a fibrotic phenotype is proposed.The diagnosis of HP is made by high-resolution computed tomography (HRCT) of the lung, evaluation of possible antigen exposure, and bronchoscopy with bronchoalveolar lavage and, if necessary, forceps biopsy. If the diagnosis is inconclusive, transbronchial cryobiopsy or surgical lung biopsy may need to follow. A multidisciplinary board is critical in making the diagnosis.

Club Cells Are the Primary Target for Permethrin-Induced Mouse Lung Tumor Formation.

Permethrin has been shown to increase lung adenomas in female CD-1 mice, but not in male mice or Wistar rats. The proposed mode of action (MOA) for permethrin-induced female mouse lung tumor formation involves morphological changes in Club cells; increased Club cell proliferation; increased Club cell hyperplasia, and lung tumor formation. In this study, the treatment of female CD-1 mice with tumorigenic doses (2500 and 5000 ppm) of permethrin, but not with a nontumorigenic dose (20 ppm), for 14 and/or 28 days increased Club cell replicative DNA synthesis. Global gene expression analysis of female mouse lung samples demonstrated that permethrin treatment up-regulated 3 genes associated with cell proliferation, namely aldehyde dehydrogenase 3a1 (Aldh3a1), oxidative stress-induced growth inhibitor 1, and thioredoxin reductase 1. Treatment with 2500 and 5000 ppm, but not 20 ppm, permethrin for 7 days produced significant increases in mRNA levels of these 3 genes. Immunohistochemical analysis demonstrated that Club cell secretory protein, CYP2F2, and ALDH3A1 colocalized in Club cells; confirmed by flow cytometry analysis of lung cells employing KI67 as a cell proliferation marker. Overall, the present data extend the proposed MOA by demonstrating that Club cells are the primary initial target of permethrin administration in female mouse lungs. As humans are quantitatively much less sensitive to agents that increase Club cell proliferation and lung tumor formation in mice, it is most likely that permethrin could not produce lung tumors in humans. This conclusion is supported by available negative epidemiological data from several studies.

Club cell-specific role of programmed cell death 5 in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) causes progressive fibrosis and worsening pulmonary function. Prognosis is poor and no effective therapies exist. We show that programmed cell death 5 (PDCD5) expression is increased in the lungs of patients with IPF and in mouse models of lung fibrosis. Lung fibrosis is significantly diminished by club cell-specific deletion of Pdcd5 gene. PDCD5 mediates ß-catenin/Smad3 complex formation, promoting TGF-ß-induced transcriptional activation of matricellular genes. Club cell Pdcd5 knockdown reduces matricellular protein secretion, inhibiting fibroblast proliferation and collagen synthesis. Here, we demonstrate the club cell-specific role of PDCD5 as a mediator of lung fibrosis and potential therapeutic target for IPF.

Club Cell Loss as a Feature of Bronchiolization in ILD.

Background: Distal airway metaplasia may precede honeycombing in progressive fibrosing interstitial lung disease (ILD). The SCGB1A1+ bronchiolar-specific club cell may play a role in this aberrant regenerative process. Objective: To assess the presence of club cells in the small airways of patients suffering from ILD. Methods: Small airways (internal diameter <2 mm) in lung samples [surgical lung biopsy (SLB) and/or transbronchial lung cryobiopsy (TBLC)] from 14 patients suffering from ILD and 10 controls were morphologically assessed and stained for SCGB1A1. SCGB1A1 was weighted by epithelial height as a marker of airway generation (SCGB1A1/EH). Correlations between clinical, functional, and high-resolution CT (HRCT) prognostic factors and histomorphometry were assessed. Results: Small airways from samples with ILD patterns were significantly less dense in terms of SCGB1A1+ cells [0.064 (0.020-0.172)] as compared to controls' sample's small airways [0.393 (0.082-0.698), p < 0.0001]. Usual interstitial pneumonia (UIP) patterns most frequently contained small airways with limited or absent SCGB1A1 expression (SCGB1A1/EH <0.025): UIP (18/33; 55%) as compared with non-UIP patterns (4/31; 13%) or controls (0/29; 0%): p < 0.0001. In addition, correlations with HRCT indicated a significant negative relationship between SCGB1A1 and bronchiectasis as a feature of bronchiolization (Rho -0.63, p < 0.001) and a positive relationship with both forced vital capacity (FVC) and Hounsfield unit (HU)-distribution pattern in kurtosis (Rho 0.38 and 0.50, respectively, both p < 0.001) as markers of fibrotic changes. Conclusion: Compared with controls, the small airways of patients with ILD more often lack SCGB1A1, especially so in UIP. Low densities of SCGB1A1-marked cells correlate with bronchiectasis and fibrotic changes. Further research investigating SCGB1A1 staining as a pathological feature of the bronchiolization process is merited.

AKT1 Mutations in Peripheral Bronchiolar Papilloma: Glandular Papilloma and Mixed Squamous Cell and Glandular Papilloma Is Distinct From Bronchiolar Adenoma.

Glandular papilloma (GP) and mixed squamous cell and glandular papilloma (MP) are rare benign pulmonary tumors occurring in the bronchi. Bronchiolar adenoma (BA) was recently characterized as a pulmonary tumor exhibiting alveolar spread. Both GP/MP and BA are composed of a mixture of glandular, ciliated, squamous, and basal cells. We aimed to clarify whether GP/MP and BA represent the same tumor. We evaluated the detailed histologic characteristics of 11 cases involving pulmonary peripheral tumors that exhibited histologic features of GP/MP or BA, and performed genetic analyses using targeted panel sequencing, allele-specific polymerase chain reaction, and digital polymerase chain reaction. Histologically, 4 and 7 tumors were classified as GP/MP and BA, respectively. GP/MP showed endobronchiolar papillary growth with a pseudostratified or stratified epithelium. In contrast, 5 BAs showed a predominant flat structure with a bilayered or pseudostratified epithelium, whereas 2 BAs showed a GP/MP-like papillary architecture. The mean epithelial thickness in each tumor was significantly larger in GP/MPs and BAs with a GP/MP-like morphology (103 to 242 µm) than in flat-predominant BA (23 to 47 µm, P=0.0010). AKT1 E17K mutations were detected in all GP/MPs and BAs with GP/MP-like morphology but were absent in the 5 flat-predominant BAs. AKT1 mutations were always concurrent with BRAF or HRAS mutations, and the variant allele frequency or percentage of mutant copies of AKT1 mutations was equal to those of BRAF or HRAS mutations. GP/MPs are characterized by AKT1 mutations concurrent with BRAF or HRAS mutations. Peribronchiolar papillary tumors with AKT1 mutations may also be classified as GP/MP.

Bronchiolitis obliterans syndrome is associated with increased senescent lymphocytes in the small airways.

BACKGROUND: Immunosuppression therapy is ineffective at preventing bronchiolitis obliterans syndrome (BOS), primarily a disease of the small airways (SAs). Our previous reports show increased senescent CD28null T and natural killer T (NKT)-like cells in the peripheral blood of patients with BOS and increased cytotoxic, proinflammatory lymphocytes in the SAs. We hypothesized that the cytotoxic, proinflammatory lymphocytes in the SAs would be steroid-resistant senescent CD28null lymphocytes. METHODS: Intracellular cytotoxic mediator granzyme B, interferon (IFN)-γ and tumor necrosis factor (TNF)-α proinflammatory cytokines, and CD28 were measured in the blood, bronchoalveolar lavage, large airway, and SA brushing T and NKT-like cells from 10 patients with BOS, 11 stable lung transplant recipients, and 10 healthy age-matched controls. SA brushings were cultured in the presence of ±1 µmol/liter prednisolone, ±5 mg/liter theophylline, and ±2.5 ng/ml cyclosporine A, and IFN-γ and TNF-α proinflammatory cytokines were assessed using flow cytometry. RESULTS: Increased SA CD28null T and NKT-like cells were identified in patients with BOS compared with that in the controls and stable transplant recipients. Loss of CD28 was associated with increased T and NKT-like cells expressing granzyme B, IFN-γ, and TNF-α. Loss of CD28 expression by CD8+ T cells was significantly associated with forced expiratory volume in 1 sec (R = 0.655, p = 0.006) and with time after transplantation (R = -0.552, p = 0.041). Treatment with prednisolone + theophylline + cyclosporin A inhibited IFN-γ and TNF-α production by SA CD28null CD8+ T and NKT-like cells additively. CONCLUSIONS: BOS is associated with the loss of CD28 in SA cytotoxic, proinflammatory senescent T and NKT-like lymphocytes. Treatment options that target the proinflammatory nature of these cells in the SAs may improve graft survival.

IL-33-ST2 axis regulates myeloid cell differentiation and activation enabling effective club cell regeneration.

Evidence points to an indispensable function of macrophages in tissue regeneration, yet the underlying molecular mechanisms remain elusive. Here we demonstrate a protective function for the IL-33-ST2 axis in bronchial epithelial repair, and implicate ST2 in myeloid cell differentiation. ST2 deficiency in mice leads to reduced lung myeloid cell infiltration, abnormal alternatively activated macrophage (AAM) function, and impaired epithelial repair post naphthalene-induced injury. Reconstitution of wild type (WT) AAMs to ST2-deficient mice completely restores bronchial re-epithelialization. Central to this mechanism is the direct effect of IL-33-ST2 signaling on monocyte/macrophage differentiation, self-renewal and repairing ability, as evidenced by the downregulation of key pathways regulating myeloid cell cycle, maturation and regenerative function of the epithelial niche in ST2-/- mice. Thus, the IL-33-ST2 axis controls epithelial niche regeneration by activating a large multi-cellular circuit, including monocyte differentiation into competent repairing AAMs, as well as group-2 innate lymphoid cell (ILC2)-mediated AAM activation.

First case of bronchiolar adenoma lined purely by mucinous luminal cells with molecular analysis: A case report.

RATIONALE: Bronchiolar adenoma (BA) is a newly designated rare entity of the lung, including both the currently designated ciliated muconodular papillary tumor (CMPT) and so-called non-classic CMPT. The most prominent histological feature of BAs is the bilayered cell structures composed of the continuous basal cell layer and the luminal layer which consists of different proportion of mucinous cells, ciliated cells, Clara cells and/or type II pneumocytes. BA purely covered by mucinous cells without other components in the luminal layer has never been reported. PATIENT CONCERNS: An 82-year-old female patient was detected a 0.8 cm ground glass nodule in the left lower lobe of the lung. DIAGNOSES: The serum levels of tumor markers were normal. INTERVENTIONS: The patient underwent a segmentectomy of the left lower lobe. OUTCOMES: The postoperative pathological diagnosis was BA. Molecular analysis revealed that the tumor harbored ALK rearrangement and BRAF mutations simultaneously. There was no recurrence in 17 months of follow-up. LESSONS: BA can be lined only by mucinous cells, without any cuboidal and/or ciliated cells in the surface layer. This sets a dangerous pitfall in differentiation diagnosis with invasive mucinous adenocarcinoma especially during intraoperative frozen pathological diagnosis.

Pathology of Idiopathic Pulmonary Fibrosis Assessed by a Combination of Microcomputed Tomography, Histology, and Immunohistochemistry.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease with the histology of usual interstitial pneumonia (UIP). Although the pathologist's visual inspection is central in histologic assessments, three-dimensional microcomputed tomography (microCT) assessment may complement the pathologist's scoring. We examined associations between the histopathologic features of UIP and IPF in explanted lungs and quantitative microCT measurements, including alveolar surface density, total lung volume taken up by tissue (%), and terminal bronchiolar number. Sixty frozen samples from 10 air-inflated explanted lungs with severe IPF and 36 samples from 6 donor control lungs were scanned with microCT and processed for histologic analysis. An experienced pathologist scored three major UIP criteria (patchy fibrosis, honeycomb, and fibroblastic foci), five additional pathologic changes, and immunohistochemical staining for CD68-, CD4-, CD8-, and CD79a-positive cells, graded on a 0 to 3+ scale. The alveolar surface density and terminal bronchiolar number decreased and the tissue percentage increased in lungs with IPF compared with controls. In lungs with IPF, lower alveolar surface density and higher tissue percentage were correlated with greater scores of patchy fibrosis, fibroblastic foci, honeycomb, CD79a-positive cells, and lymphoid follicles. A decreased number of terminal bronchioles was correlated with honeycomb score but not with the other scores. The three-dimensional microCT measurements reflect the pathological UIP and IPF criteria and suggest that the reduction in the terminal bronchioles may be associated with honeycomb cyst formation.

Dysregulation of club cell biology in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic fibrotic lung disease with an irreversible decline of lung function. "Bronchiolization", characterized by ectopic appearance of airway epithelial cells in the alveolar regions, is one of the characteristic features in the IPF lung. Based on the knowledge that club cells are the major epithelial secretory cells in human small airways, and their major secretory product uteroglobin (SCGB1A1) is significantly increased in both serum and epithelial lining fluid of IPF lung, we hypothesize that human airway club cells contribute to the pathogenesis of IPF. By assessing the transcriptomes of the single cells from human lung of control donors and IPF patients, we identified two SCGB1A1+ club cell subpopulations, highly expressing MUC5B, a significant genetic risk factor strongly associated with IPF, and SCGB3A2, a marker heterogeneously expressed in the club cells, respectively. Interestingly, the cellular proportion of SCGB1A1+MUC5B+ club cells was significantly increased in IPF patients, and this club cell subpopulation highly expressed genes related to mucous production and immune cell chemotaxis. In contrast, though the cellular proportion did not change, the molecular phenotype of the SCGB1A1+SCGB3A2high club cell subpopulation was significantly altered in IPF lung, with increased expression of mucins, cytokine and extracellular matrix genes. The single cell transcriptomic analysis reveals the cellular and molecular heterogeneity of club cells, and provide novel insights into the biological functions of club cells in the pathogenesis of IPF.

Endothelial activation and dysfunction in metabolic syndrome, type 2 diabetes and coronavirus disease 2019.

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 infection is a serious global concern. Increased morbidity and mortality is associated with older age, male gender, cardiovascular disease, diabetes, and smoking. As COVID-19 spreads from coastal borders, both state to state and country to country, our understanding of its pathophysiology has evolved. Age and type 2 diabetes mellitus (T2DM) play especially important roles in COVID-19 progression. T2DM is an age-related disease associated with metabolic syndrome, obesity, insulin resistance (hyperinsulinemia), hyperlipidemia, hypertension, hyperglycemia, and endothelial activation and dysfunction. This review evaluates the relationships and intersection between endothelial cell activation and dysfunction in T2DM and COVID-19. COVID-19 induces multiple injuries of the terminal bronchioles and alveolar blood-gas barrier and associated ultrastructural tissue remodeling. COVID-19 may unmask multiple vulnerabilities associated with T2DM including damage to the endothelial glycocalyx and multiple end-organ macro and microvascular diseases. Unmasking existing vulnerabilities in diabetic patients with COVID-19 is important. Globally, we must come together to better understand why T2DM is associated with increased COVID-19 morbidity and mortality.