CD81 Controls Beige Fat Progenitor Cell Growth and Energy Balance via FAK Signaling.

Adipose tissues dynamically remodel their cellular composition in response to external cues by stimulating beige adipocyte biogenesis; however, the developmental origin and pathways regulating this process remain insufficiently understood owing to adipose tissue heterogeneity. Here, we employed single-cell RNA-seq and identified a unique subset of adipocyte progenitor cells (APCs) that possessed the cell-intrinsic plasticity to give rise to beige fat. This beige APC population is proliferative and marked by cell-surface proteins, including PDGFRα, Sca1, and CD81. Notably, CD81 is not only a beige APC marker but also required for de novo beige fat biogenesis following cold exposure. CD81 forms a complex with αV/ß1 and αV/ß5 integrins and mediates the activation of integrin-FAK signaling in response to irisin. Importantly, CD81 loss causes diet-induced obesity, insulin resistance, and adipose tissue inflammation. These results suggest that CD81 functions as a key sensor of external inputs and controls beige APC proliferation and whole-body energy homeostasis.

The diagnostic impact of fractional exhaled nitric oxide for asthmatic cough in nontuberculous mycobacterial pulmonary disease.

BACKGROUND: Measurement of exhaled nitric oxide (FeNO) is a potentially useful diagnostic test for asthma. However, no study has explored the relationship between FeNO and respiratory symptoms of nontuberculous mycobacterial pulmonary disease (NTM-PD) complicated with asthma. The objective of this study was to assess the utility of measuring FeNO levels in patients with NTM-PD complicated by asthma. METHODS: In this single-center retrospective cohort study, 140 NTM-PD patients with FeNO measured were enrolled. We selected NTM-PD patients who complicated with asthma as the NTM+BA group, defined using the following criteria: NTM patients with symptoms consistent with asthma, and NTM patients with symptomatic improvement after diagnostic therapy with ICS ± a long-acting beta 2-agonist (LABA). We then calculated a diagnostic cutoff point to distinguish between the NTM+BA groups and the NTM groups (all others). High-resolution computed tomography (HRCT) images were evaluated using the CT scoring system and their association with FeNO was examined. RESULTS: A total of 89 patients were included in the study. (31 in the NTM+BA group and 58 in the NTM group). Compared with the NTM group, the NTM+BA group had higher rates of allergic disease (51.6% vs. 22.4%; p=0.0085) and higher FeNO values (median, 23 [interquartile range {IQR}, 15.0-43.0] ppb vs. median, 17 [IQR, 11.8-23.0] ppb; p=0.015). With diagnostic asthma care using mainly ICS/LABA with reference to the FeNO, most patients (91.0%, 20/22) in the NTM-preceding subgroup in the NTM+BA group demonstrated a prompt improvement of their symptoms and AFB culture findings did not worsen (Culture positive rate (%): Pre-treatment: 59.1% vs. Post-treatment: 40.9%, p=0.3660) at 6 months after starting diagnostic therapy. The optimal diagnostic cutoff point of FeNO to distinguish between the two groups was calculated as 21.5 ppb by the ROC curve (sensitivity 75%, specificity 71.93%, p<0.0001; area under the curve: 0.7989). No significant correlation was observed between FeNO and the severity of CT images in the patients. CONCLUSIONS: A certain number of patients with NTM-PD showed exacerbated respiratory symptoms due to asthmatic complications. Elevated FeNO levels suggest asthma complications, even in patients with NTM.

Laryngeal widening and adequate ventilation by expiratory pressure load training improve aerobic capacity in COPD: a randomised controlled trial.

RATIONALE: Despite strategies acting on peripheral airway obstruction in chronic obstructive pulmonary disease (COPD), exercise intolerance remains inadequately improved. We hypothesised that laryngeal narrowing is a potential treatment target of expiratory pressure load training (EPT) to improve exercise intolerance in COPD. METHODS: The effect of 3-month EPT was assessed in 47 patients with COPD divided into Global Initiative for Chronic Obstructive Lung Disease (GOLD) mild-to-moderate (I-II) and severe-to-very severe (III-IV), randomly allocating 1:1 to EPT or control groups. The primary outcome was endurance time in the constant work rate exercise test in GOLD III-IV patients. RESULTS: Compared with controls, EPT increased: (1) endurance time, with estimated treatment effect: +703 (95% CI: 379 to 1031) s, p=0.0008 (GOLD I-II); +390 (95% CI: 205 to 574) s, p=0.0006 (GOLD III-IV); (2) peak oxygen uptake (p=0.0086 in GOLD I-II; p=0.0004 in GOLD III-IV); (3) glottic dilatation ratio at maximum collapse on laryngoscopy in the submaximal exercise (p=0.0062 in GOLD I-II; p=0.0001 in GOLD III-IV); and (4) the inflection point of expiratory tidal volume relative to minute ventilation during the incremental exercise (p=0.0015 in GOLD I-II; p=0.0075 in GOLD III-IV). Across GOLD grades, the responses of glottic dilatation ratio at maximum collapse and the expiratory tidal volume at the inflection point were selected as more influential variables correlating with the improvement in peak oxygen uptake and endurance time, respectively. CONCLUSION: These results show that EPT improved aerobic capacity and endurance time with larger laryngeal widening and adequate ventilation despite advanced COPD. TRIAL REGISTRATION NUMBER: UMIN000041250.

MGIT-seq for the Identification of Nontuberculous Mycobacteria and Drug Resistance: a Prospective Study.

Because nontuberculous mycobacterial pulmonary disease is a considerable health burden, a simple and clinically applicable analytical protocol enabling the identification of subspecies and drug-resistant disease is required to determine the treatment strategy. We aimed to develop a simplified workflow consisting only of direct sequencing of mycobacterial growth indicator tube cultures (MGIT-seq). In total, 138 patients were prospectively enrolled between April 2021 and May 2022, and culture-positive MGIT broths were subjected to sequencing using MinION, a portable next-generation sequencer. Sequence analysis was conducted to identify species using core genome multilocus sequence typing and to predict macrolide and amikacin (AMK) resistance based on previously reported mutations in rrl, rrs, and erm(41). The results were compared to clinical tests for species identification and drug susceptibility. A total of 116 patients with positive MGIT cultures were included in the analysis. MGIT-seq yielded 99.1% accuracy in species-level identification and identified 98 isolates (84.5%) at the subspecies level. Macrolide and AMK resistance were detected in 19.4% and 1.9% of Mycobacterium avium complex (MAC) and Mycobacterium abscessus isolates. The predicted macrolide and AMK resistance was consistent with the results of conventional drug susceptibility tests, with specificities of 97.6% and 100.0%, respectively. Direct MGIT-seq has achieved comprehensive identification and drug resistance detection of nontuberculous mycobacteria, which could be applicable to determine the treatment strategy by a single test in clinical practice.

Chronic Pulmonary Disease Caused by Tsukamurella toyonakaense.

Unidentified Mycobacterium species are sometimes detected in respiratory specimens. We identified a novel Tsukamurella species (Tsukamurella sp. TY48, RIMD 2001001, CIP 111916T), Tsukamurella toyonakaense, from a patient given a misdiagnosis of nontuberculous mycobacterial pulmonary disease caused by unidentified mycobacteria. Genomic identification of this Tsukamurella species helped clarify its clinical characteristics and epidemiology.

Mycobacterium senriense sp. nov., a slowly growing, non-scotochromogenic species, isolated from sputum of an elderly man.

A slowly growing mycobacteria, identified as strain TY59T, was isolated from sputum of an elderly man with pneumonia. Sequencing of the 16S rRNA gene indicated that this strain was similar to members of the Mycobacterium avium complex and closely related species. Strain TY59T has highest 16S rRNA gene sequence similarities to the type strains of Mycobacterium colombiense (99.80 % sequence similarity), Mycobacterium vulneris (99.74 %), Mycobacterium timonense (99.54 %), Mycobacterium avium subsp. avium (99.54 %) and Mycobacterium avium subsp. silvaticum (99.54 %). Analysis of the internal transcribed spacer (ITS) and DNA-directed RNA polymerase subunit beta (rpoB) sequences gave similar results to the 16S rRNA gene analysis. The closest species to strain TY59T were M. colombiense and M. vulneris with 97.90-98.25 % identity in ITS and 96.4-96.6 % in rpoB. The strain's 65 kDa heat shock protein (hsp65) gene was different from those of M. vulneris, M. colombiense and M. avium subsp. silvaticum with 72.4-74.2 % identity. Average nucleotide identity results showed a 93.4 % match to M. vulneris as the maximum value. Phenotypically, the non-chromogenicity, rough colonies, growth at 42 °C, negative results for nitrate reduction, ß-glucosidase and Tween 80 hydrolysis, and positive results for catalase activity set this strain apart from closely related species. We propose that Mycobacterium senriense sp. nov. is a novel species of slowly growing mycobacteria. The type strain is TY59T (RIMD 1371001T=CIP 111917T).

Induced hepatic stellate cell integrin, α8ß1, enhances cellular contractility and TGFß activity in liver fibrosis.

No effective therapy exists for fatal fibrosis. New therapeutic targets are needed for hepatic fibrosis because the incidence keeps increasing. The activation and differentiation of fibroblasts into myofibroblasts that causes excessive matrix deposition is central to fibrosis. Here, we investigated whether (and which) integrin receptors for matrix proteins activate hepatic stellate cells (HSCs). First, integrin α-subunits were investigated systematically for their expression over the course of HSC activation and their distribution on fibroblasts and other systemic primary cells. The most upregulated in plate culture-activated HSCs and specifically expressed across fibroblast linages was the α8 subunit. An anti-α8 neutralizing mAb was evaluated in three different murine fibrosis models: for cytotoxic (CCl4 treatment), non-alcoholic steatohepatitis-associated and cholestatic fibrosis. In all models, pathology and fibrosis markers (hydroxyproline and α-smooth muscle actin) were improved following the mAb injection. We also CCl4 -treated mice with inducible Itga8-/-; these mice were protected from increased hydroxyproline levels. Furthermore, ITGA8 was upregulated in specimens from 90 patients with liver fibrosis, indicating the relevance of our findings to liver fibrosis in people. Mechanistically, inhibition or ligand engagement of HSC α8 suppressed and enhanced myofibroblast differentiation, respectively, and HSC/fibroblast α8 activated latent TGFß. Finally, integrin α8ß1 potentially fulfils the growing need for anti-fibrotic drugs and is an integrin not to be ignored. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

Characteristic chest CT findings for progressive cavities in Mycobacterium avium complex pulmonary disease: a retrospective cohort study.

BACKGROUND: Although cavities are an important finding in Mycobacterium avium complex pulmonary disease (MAC-PD), there is little information regarding the types of cavities that indicate disease progression. This study was performed to identify cavity characteristics that were associated with disease progression in patients with MAC-PD. METHODS: This retrospective cohort study included 97 patients presenting with MAC-PD with cavities between December 2006 and June 2016. We compared initial and final computed tomography (CT) findings, classified 52 and 45 patients in the progressive and non-progressive cavity groups, respectively, and examined the progression-related imaging features in initial CT images. A progressive cavity was defined by more than two-fold increase in internal diameter or emergence of a new cavity around the initial cavity. RESULTS: Patients in the progressive group were older (p < 0.001), had a lower body mass index (p = 0.043), and showed higher diabetes complication rates (p = 0.005). The initial CT in the progressive group showed a longer maximum internal diameter of the cavity (p < 0.001) and higher rates of cavities close to the chest wall (p < 0.001), multiple cavities (p = 0.023), consolidation around the cavity (p < 0.001), atelectasis (p = 0.011), and pleural thickening (p < 0.001). Multivariable logistic regression analysis revealed that the maximum internal diameter of the cavity (odds ratio [OR]: 1.11, 95% confidence interval [CI]: 1.02-1.21; p=0.012) and consolidation around the cavity (OR: 16.15, 95% CI: 4.05-64.46; p < 0.001) were significantly associated with progressive cavities. In cavities with a maximum internal diameter of ≥10 mm and simultaneous consolidation, the probability of progression was as high as 96.2%. The 10-year mortality rates in the progressive and non-progressive cavity groups were 46.7 and 9.8% (p < 0.001), respectively, while the 10-year respiratory failure rates were 28.1 and 0%, respectively (p < 0.001). CONCLUSIONS: Large cavity size and consolidation on CT showed strong relationships with disease progression, which led to respiratory failure and high mortality rate.

The impact of adjuvant surgical treatment of nontuberculous mycobacterial pulmonary disease on prognosis and outcome.

BACKGROUND: Lung resection in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) has been reported to be associated with favorable outcomes. However, little is known regarding the risk and prognostic factors for refractory and recurrent cases. We aimed to evaluate the overall impact and benefit of adjuvant lung surgery by comparing NTM-PD patients who underwent adjuvant lung resection with those treated exclusively with antibiotics. We also investigated the efficacy of serum IgA antibody against glycopeptidolipid (GPL) core antigen (GPL core antibody) to monitor disease activity and predict the recurrence of disease after adjuvant lung resection. METHODS: We retrospectively evaluated the clinical characteristics and surgical outcomes of 35 patients surgically treated for NTM-PD. Furthermore, we compared surgically treated patients and control patients treated exclusively with antibiotics who were matched statistically 1:1 using a propensity score calculated from age, sex, body mass index, and radiologic features of disease. RESULTS: In the surgically treated patients, the median age was 58 (interquartile range, 47-65) years and 65.7% were female. Twenty-eight patients had Mycobacterium avium complex. Operations comprised four pneumonectomies, two bilobectomies, one bilobectomy plus segmentectomy, 17 lobectomies, two segmentectomies, and nine lobectomies plus segmentectomies. Postoperative complications occurred in seven patients (20%), there were no operative deaths, and 33 (94.3%) patients achieved negative sputum culture conversion. Refractory and recurrent cases were associated with remnant bronchiectasis, contralateral shadows, and positive acid-fast bacilli staining or culture. Of 28 statistically matched pairs, long-term sustained negative culture conversion was observed in 23 (82.2%) surgical group patients and in 14 (50.0%) non-surgical group patients (0.0438). The mortality rate was lower in the surgical group, but did not reach statistical significance (one in the surgical group and four in the non-surgical group, p = 0.3516). GPL core antibody was correlated with disease activity and recurrence. CONCLUSIONS: NTM-PD patients who underwent adjuvant lung resection experienced overall favorable outcomes and achieved sputum culture conversion more frequently. Long-term mortality may have been reduced by this procedure, and the level of GPL core antibody was shown to be a good clinical indicator of disease activity after surgery.

Pulmonary disease caused by a newly identified mycobacterium: Mycolicibacterium toneyamachuris: a case report.

BACKGROUND: Non-tuberculous mycobacterial pulmonary disease (NTM-PD) is becoming a significant health burden. Recent advances in analysis techniques have allowed the accurate identification of previously unknown NTM species. Here, we report a case of NTM-PD caused by a newly identified mycobacteria in an immunocompetent patient. CASE PRESENTATION: A 44-year-old woman was referred to our hospital due to the frequent aggravation of her chronic respiratory symptoms, with NTM-PD-compatible computed tomography findings. Unidentified mycobacterium was repeatedly isolated from respiratory specimens and we diagnosed her as NTM-PD of unidentified mycobacterium. Subsequent whole-genome analysis revealed that the unidentified mycobacterium was a novel mycobacterium genetically close to Mycolicibacterium mucogenicum. We started combination therapy with clarithromycin, moxifloxacin, amikacin, and imipenem/cilastatin, referring to drug sensitivity test results and observed its effect on M. mucogenicum infection. Her symptoms and radiological findings improved significantly. CONCLUSION: We report a case of NTM-PD caused by a newly identified mycobacteria, Mycolicibacterium toneyamachuris, genetically close to M. mucogenicum. This pathogenic mycobacterium showed different characteristics from M. mucogenicum about clinical presentation and drug sensitivity. The clinical application of genomic sequencing will advance the identification and classification of pathogenic NTM species, and enhance our understanding of mycobacterial diseases.

Natural Autoantibodies in Chronic Pulmonary Diseases.

In autoantibody-mediated autoimmune diseases, pathogenic autoantibodies generated by a failure of central or peripheral tolerance, have different effects mediated by a variety of mechanisms. Interestingly, even non-autoimmune chronic diseases have a set of disease-specific natural autoantibodies that are maintained for a long time. Because most of these natural autoantibodies target intracellular proteins or long non-coding RNAs, they are speculated to be non-pathological and have some important as yet unrecognized physiological functions such as debris clearance. Recently, we revealed a set of disease-specific natural autoantibodies of chronic pulmonary diseases with unknown etiology by protein arrays that enable detection of specific autoantibodies against >8000 targets. Surprisingly, some of the targeted antigens of disease-specific autoantibodies were subsequently reported by other laboratories as strongly associated with the disease, suggesting that these antigens reflect the pathology of each disease. Furthermore, some of these autoantibodies that target extracellular antigens might modify the original course of each disease. Here, we review the disease-specific natural autoantibodies of chronic pulmonary diseases, including chronic fibrosing idiopathic interstitial pneumonias, sarcoidosis, and autoimmune pulmonary alveolar proteinosis, and discuss their utility and effects.

Pharmacologic Blockade of αvß1 Integrin Ameliorates Renal Failure and Fibrosis In Vivo.

Activated fibroblasts are deemed the main executors of organ fibrosis. However, regulation of the pathologic functions of these cells in vivo is poorly understood. PDGF receptor ß (PDGFRß) is highly expressed in activated pericytes, a main source of fibroblasts. Studies using a PDGFRß promoter-driven Cre system to delete αv integrins in activated fibroblasts identified these integrins as core regulators of fibroblast activity across solid organs, including the kidneys. Here, we used the same PDGFRß-Cre line to isolate and study renal fibroblasts ex vivo We found that renal fibroblasts express three αv integrins, namely αvß1, αvß3, and αvß5. Blockade of αvß1 prevented direct binding of fibroblasts to the latency-associated peptide of TGF-ß1 and prevented activation of the latent TGF-ß complex. Continuous administration of a recently described potent small molecule inhibitor of αvß1, compound 8, starting the day of unilateral ureteral obstruction operation, inhibited collagen deposition in the kidneys of mice 14 days later. Compound 8 also effectively attenuated renal failure, as measured by BUN levels in mice fed an adenine diet known to cause renal injury followed by fibrosis. Inhibition of αvß1 integrin could thus hold promise as a therapeutic intervention in CKD characterized by renal fibrosis.

Transforming growth factor-ß plays divergent roles in modulating vascular remodeling, inflammation, and pulmonary fibrosis in a murine model of scleroderma.

The efficacy and feasibility of targeting transforming growth factor-ß (TGFß) in pulmonary fibrosis and lung vascular remodeling in systemic sclerosis (SSc) have not been well elucidated. In this study we analyzed how blocking TGFß signaling affects pulmonary abnormalities in Fos-related antigen 2 (Fra-2) transgenic (Tg) mice, a murine model that manifests three important lung pathological features of SSc: fibrosis, inflammation, and vascular remodeling. To interrupt TGFß signaling in the Fra-2 Tg mice, we used a pan-TGFß-blocking antibody, 1D11, and Tg mice in which TGFß receptor type 2 (Tgfbr2) is deleted from smooth muscle cells and myofibroblasts (α-SMA-CreER;Tgfbr2flox/flox). Global inhibition of TGFß by 1D11 did not ameliorate lung fibrosis histologically or biochemically, whereas it resulted in a significant increase in the number of immune cells infiltrating the lungs. In contrast, 1D11 treatment ameliorated the severity of pulmonary vascular remodeling in Fra-2 Tg mice. Similarly, genetic deletion of Tgfbr2 from smooth muscle cells resulted in improvement of pulmonary vascular remodeling in the Fra-2 Tg mice, as well as a decrease in the number of Ki67-positive vascular smooth muscle cells, suggesting that TGFß signaling contributes to development of pulmonary vascular remodeling by promoting the proliferation of vascular smooth muscle cells. Deletion of Tgfbr2 from α-smooth muscle actin-expressing cells had no effect on fibrosis or inflammation in this model. These results suggest that efforts to target TGFß in SSc will likely require more precision than simply global inhibition of TGFß function.

Fra-2 negatively regulates postnatal alveolar septation by modulating myofibroblast function.

Mice that globally overexpress the transcription factor Fos-related antigen-2 (Fra-2) develop extensive pulmonary fibrosis and pulmonary vascular remodeling. To determine if these phenotypes are a consequence of ectopic Fra-2 expression in vascular smooth muscle cells and myofibroblasts, we generated mice that overexpress Fra-2 specifically in these cell types (α-SMA-rtTA;tetO-Fra-2). Surprisingly, these mice did not develop vascular remodeling or pulmonary fibrosis but did develop a spontaneous emphysema-like phenotype characterized by alveolar enlargement. Secondary septa formation is an important step in the normal development of lung alveoli, and α-smooth muscle actin (SMA)-expressing fibroblasts (myofibroblasts) play a crucial role in this process. The mutant mice showed reduced numbers of secondary septa at postnatal day 7 and enlarged alveolae starting at postnatal day 12, suggesting impairment of secondary septa formation. Lineage tracing using α-SMA-rtTA mice crossed to a floxed TdTomato reporter revealed that embryonic expression of α-SMA Cre marked a population of cells that gave rise to nearly all alveolar myofibroblasts. Comprehensive transcriptome analyses (RNA sequencing) demonstrated that the overwhelming majority of genes whose expression was significantly altered by overexpression of Fra-2 in myofibroblasts encoded secreted proteins, components of the extracellular matrix (ECM), and cell adhesion-associated genes, including coordinate upregulation of pairs of integrins and their principal ECM ligands. In addition, primary myofibroblasts isolated from the mutant mice showed reduced migration capacity. These findings suggest that Fra-2 overexpression might impair myofibroblast functions crucial for secondary septation, such as myofibroblast migration across alveoli, by perturbing interactions between integrins and locally produced components of the ECM.

Critical Appraisal of the Utility and Limitations of Animal Models of Scleroderma.

Scleroderma, also called systemic sclerosis (SSc), is an autoimmune connective tissue disease characterized by abnormality of the immune system, cardiovascular disorder, and fibrosis of the skin, lung, kidney, and other internal organs. Skin symptom and stiffness of the skin with accumulation of collagen cause severe disability, and cardiovascular and lung complications lead to high mortality. Despite recent progress, therapies for these complications in SSc are limited and the underlying mechanisms are poorly understood. Animal models are one strategy to identify molecular mechanisms and pathways underlying these complications of SSc and could provide a mechanistic basis for a design of clinical trials. However, although several animal models have been reported to reproduce some aspects of SSc, none of them recapitulates all of the pathological features of SSc. In this review, we describe previously reported animal models of scleroderma and discuss their utility and limitations in efforts to understand the mechanisms underlying scleroderma and develop new treatments for this disease.

Deletion of tetraspanin CD9 diminishes lymphangiogenesis in vivo and in vitro.

Tetraspanins have emerged as key players in malignancy and inflammatory diseases, yet little is known about their roles in angiogenesis, and nothing is known about their involvement in lymphangiogenesis. We found here that tetraspanins are abundantly expressed in human lymphatic endothelial cells (LEC). After intrathoracic tumor implantation, metastasis to lymph nodes was diminished and accompanied by decreased angiogenesis and lymphangiogenesis in tetraspanin CD9-KO mice. Moreover, lymphangiomas induced in CD9-KO mice were less pronounced with decreased lymphangiogenesis compared with those in wild-type mice. Although mouse LEC isolated from CD9-KO mice showed normal adhesion, lymphangiogenesis was markedly impaired in several assays (migration, proliferation, and cable formation) in vitro and in the lymphatic ring assay ex vivo. Consistent with these findings in mouse LEC, knocking down CD9 in human LEC also produced decreased migration, proliferation, and cable formation. Immunoprecipitation analysis demonstrated that deletion of CD9 in LEC diminished formation of functional complexes between VEGF receptor-3 and integrins (α5 and α9). Therefore, knocking down CD9 in LEC attenuated VEGF receptor-3 signaling, as well as downstream signaling such as Erk and p38 upon VEGF-C stimulation. Finally, double deletion of CD9/CD81 in mice caused abnormal development of lymphatic vasculature in the trachea and diaphragm, suggesting that CD9 and a closely related tetraspanin CD81 coordinately play an essential role in physiological lymphangiogenesis. In conclusion, tetraspanin CD9 modulates molecular organization of integrins in LEC, thereby supporting several functions required for lymphangiogenesis.

Body positioning-related laryngeal narrowing pattern and expiratory mechanical constraints in advanced chronic obstructive pulmonary disease: A case report.

We previously reported that laryngeal widening led to improved exercise tolerance in COPD. However, it is not clear whether laryngeal narrowing occurs as a compensatory response to tracheal movement or is affected by posture. Here, we report the case of an advanced COPD patient whose more prolonged expiration in a head-forward leaning position compared with that in a neck-extended position occurred with an excessive duration of severe laryngeal narrowing without tracheal obstruction, which led to exercise intolerance with expiratory mechanical constraints. This case provided useful insights into the regulation of the upper airway with body positioning for improving exercise tolerance.

Validation of noninvasive morphological and diffusion imaging in mouse emphysema by micro-computed tomography and hyperpolarized (129)Xe magnetic resonance imaging.

Animal disease models are pivotal in investigating the pathogenesis of emphysema and developing novel drugs, but the modalities to evaluate murine emphysema models have been of limited validity and sensitivity. In this study, we evaluated hyperpolarized (129)Xe magnetic resonance imaging (MRI) and micro-computed tomography (micro-CT) compared with traditional methods, such as plethysmography and histology. Elastase-treated mice and adiponectin knockout mice were used as murine emphysema models to evaluate these modalities. Three weeks after elastase administration, significant and heterogeneous emphysema was evaluated according to the mean linear intercept and plethysmography parameters. Notably, the distribution of low-density areas, as examined by micro-CT, correlated with the mean linear intercept and plethysmography parameters in whole lungs. These correlations were also observed in regional areas. Furthermore, we introduced hyperpolarized (129)Xe MRI, which can evaluate gas exchange between the alveoli and blood during spontaneous breathing. Parameters of gas exchange (fD) and alveolar size (Vs/Va) were significantly decreased in elastase-treated mice, and moderately correlated with the plethysmography parameters. Of importance, we could detect a decrease of the fD value in low-density areas with micro-CT, suggesting that gas exchange decreased in emphysematous lesions. Likewise, these parameters (fD and Vs/Va) were also decreased in adiponectin knockout mice, which exhibit emphysema with a homogeneous distribution. We demonstrated the feasibility of (129)Xe MRI and micro-CT in combination with traditional modalities. These noninvasive modalities provide complementary data that can be used for repeated estimations of regional gas exchange and lung morphology.

Tetraspanin CD151 protects against pulmonary fibrosis by maintaining epithelial integrity.

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a chronic pulmonary disorder of unknown etiology with few treatment options. Although tetraspanins are involved in various diseases, their roles in fibrosis have not been determined. OBJECTIVES: To investigate the role of tetraspanin CD151 in pulmonary fibrosis. METHODS: CD151 knockout (KO) mice were studied by histological, biochemical, and physiological analyses and compared with wild-type mice and CD9 KO mice. Further mechanistic analyses were performed in vitro, in vivo, and on samples from patients with IPF. MEASUREMENTS AND MAIN RESULTS: A microarray study identified an enrichment of genes involved in connective tissue disorders in the lungs of CD151 KO mice, but not in CD9 KO mice. Consistent with this, CD151 KO mice spontaneously exhibited age-related pulmonary fibrosis. Deletion of CD151 did not affect pulmonary fibroblast functions but instead degraded epithelial integrity via attenuated adhesion strength on the basement membrane; CD151-deleted alveolar epithelial cells exhibited increased α-SMA expression with activation of p-Smad2, leading to fibrotic changes in the lungs. This loss of epithelial integrity in CD151 KO lungs was further exacerbated by intratracheal bleomycin exposure, resulting in severe fibrosis with increased mortality. We also observed decreased numbers of CD151-positive alveolar epithelial cells in patients with IPF. CONCLUSIONS: CD151 is essential for normal function of alveolar epithelial cells; loss of CD151 causes pulmonary fibrosis as a result of epithelial disintegrity. Given that CD151 may protect against fibrosis, this protein represents a novel target for the treatment of fibrotic diseases.

Diagnosis and Management of Drug-Induced Interstitial Lung Disease Associated with Amikacin Liposome Inhalation Suspension in Refractory Mycobacterium Avium Complex Pulmonary Disease: A Case Report.

Amikacin liposome inhalation suspension (ALIS) is a key drug for the treatment of refractory Mycobacterium avium complex pulmonary disease (MAC-PD). Although cases of drug-induced interstitial lung disease (DIILD) by ALIS have been reported, its diagnosis is challenging due to overlapping existing pulmonary shadows, airway bleeding, exacerbation of underlying conditions, and the potential for various concurrent infections. A 72-year-old woman started treatment with ALIS for refractory MAC-PD. Three weeks later, she had a fever, cough, and appetite loss. She was hospitalized because multiple infiltrative opacities were observed on chest X-ray and chest computed tomography. Because the opacities worsened after empiric antibiotic therapy with broad-spectrum antibiotics, we initiated corticosteroid therapy, suspecting DIILD caused by ALIS, although drug lymphocyte stimulation tests for ALIS and amikacin were negative. Three days later, we found signs of improvement and quickly tapered the corticosteroids. After obtaining informed consent, we performed a drug provocation test of ALIS. Seven days later, she exhibited fever, an increased peripheral white blood cell count, and elevated serum C-reactive protein level, all of which returned to baseline 4 days after stopping ALIS, leading to a diagnosis of DIILD caused by ALIS in this patient. DIILD caused by ALIS is rare but should be carefully diagnosed to ensure that patients with refractory MAC-PD do not miss the opportunity to receive ALIS treatment.