Effect of decreased expression of latent TGF-ß binding proteins 4 on the pathogenesis of emphysema as an age-related disease.

PURPOSE: Latent TGF-ß binding protein 4 (LTBP4) is involved in the production of elastin fibers and has been implicated in LTBP4-related cutis laxa and its complication, emphysema-like changes. Various factors have been implicated in the pathogenesis of emphysema, including elastic degeneration, inflammation, cellular senescence, mitochondrial dysfunction, and decreased angiogenesis in the lungs. We investigated the association between LTBP4 and emphysema using human lung fibroblasts with silenced LTBP4 genes. METHODS: Cell contraction, elastin expression, cellular senescence, inflammation, anti-inflammatory factors, and mitochondrial function were compared between the LTBP4 small interfering RNA (siRNA) and control siRNA. RESULTS: Under the suppression of LTBP4, significant changes were observed in the following: decreased cell contractility, decreased elastin expression, increased expression of the p16 gene involved in cellular senescence, increased TNFα, decreased GSTM3 and SOD, decreased mitochondrial membrane potential, and decreased VEGF expression. Furthermore, the decreased cell contractility and increased GSTM3 expression observed under LTBP4 suppression were restored by the addition of N-acetyl-L-cysteine or recombinant LTBP4. CONCLUSION: The decreased elastin expression, cellular senescence, inflammation, decreased antioxidant activity, mitochondrial dysfunction, and decreased VEGF expression under reduced LTBP4 expression may all be involved in the destruction of the alveolar wall in emphysema. Smoking is the most common cause of emphysema; however, genetic factors related to LTBP4 expression and other factors may also contribute to its pathogenesis.

Serum MMP3 and IL1-RA levels may be useful biomarkers for detecting asthma and chronic obstructive pulmonary disease overlap in patients with asthma.

Background: Asthma and chronic obstructive pulmonary disease (COPD) overlap (ACO) is characterized by concurrent features of asthma and COPD. Since disease pathogenesis, severities, and treatments differ between asthma and ACO, it is important to differentiate them. Objective: To clarify and compare the characteristics of ACO and asthma and identify the serum biomarkers for differentiating them, especially in older patients. Methods: This study used the data of 639 participants from the nationwide cohort study, the NHOM-Asthma study, an asthma registry in Japan, with complete information on smoking history, respiratory function, and serum biomarkers. ACO was defined as the self-reported comorbidity of COPD or emphysema, or with obstructive pulmonary function and smoking history (pack-years≥10). The clinical characteristics of patients with ACO and asthma without COPD were compared. The serum biomarkers for differentiation were examined using receiver operating characteristic curves and multivariable analysis. The associations between the biomarkers and age were also analyzed. Results: Of the 639 asthma patients, 125 (19.6%) were diagnosed with ACO; these patients were older and male-dominant and had a higher prevalence of comorbidities such as hypertension, diabetes, and stroke. Among the serum biomarkers that were significantly different between ACO and asthma without COPD, the YKL-40/CHI3L1, MMP3, and IL-1RA levels showed a high area under the curve for discriminating ACO. Only the MMP3 and IL-1RA levels were significantly higher among ACO patients, regardless of age and sex; the YKL-40/CHI3L1 levels were not different due to the effect of age. Conclusion: MMP3 and IL-1RA may be useful serum biomarkers for distinguishing ACO from asthma.

Identification of ANXA2 on epithelial cells as a new receptor for secretory IgA using immunoprecipitation and mass spectrometry.

Secretory immunoglobulin A plays an important role in the protection against exogenous pathogens and antigens, but it has also been reported to have pathogenic potential. We previously found that secretory immunoglobulin A accumulated in the peripheral lungs during idiopathic pulmonary fibrosis and that transferrin receptor/CD71 was partially involved in secretory immunoglobulin A-induced inflammatory cytokine production in A549 cells. This study aimed to identify the receptor responsible for the induction of cytokine production by secretory immunoglobulin A-stimulated airway epithelial cells. To this end, immunoprecipitation followed by time-of-flight mass spectrometry and peptide mass fingerprinting were performed and Annexin A2 was detected as a novel receptor for secretory immunoglobulin A. Enzyme-linked immunosorbent assay demonstrated binding of secretory immunoglobulin A to Annexin A2, and flow cytometry showed robust expression of Annexin A2 on the surface of BEAS-2B cells, A549 cells, and normal human bronchial/tracheal epithelial cells. Experiments in A549 cells using Annexin A2 small interfering RNA and neutralizing antibodies suggested that Annexin A2 was partially involved in the production of interleukin-8/CXCL8 and C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 induced by secretory immunoglobulin A. Immunohistochemistry using lung sections revealed clear expression of Annexin A2 on airway epithelial cells, although the staining remained equivalent in idiopathic pulmonary fibrosis, asthma, and healthy control lungs. In conclusion, we identified that Annexin A2 expressed in airway epithelial cells is a novel receptor for secretory immunoglobulin A, which is involved in cytokine synthesis.

DASC-21: a novel geriatric assessment for discriminating best supportive care in older patients with inoperable advanced non-small cell lung cancer.

OBJECTIVE: This study investigated whether the Dementia Assessment Sheet for the Community-based Integrated Care System is useful for decision-making or problem detection in the treatment and care of older patients with inoperable advanced non-small cell lung cancer compared with the current standard model using performance status. METHODS: This study retrospectively examined 1595 cases admitted to the Department of Respiratory Medicine at the Tokyo Metropolitan Geriatric Hospital between 26 July 2016 and 28 January 2020. Among these, 29 and 31 patients who received pharmacotherapies and best supportive care were extracted, respectively. The performance in identifying best supportive care using the Dementia Assessment Sheet for the Community-based Integrated Care System was evaluated in comparison with performance status. The ability to detect impairments in each Dementia Assessment Sheet for the Community-based Integrated Care System domain was also assessed. RESULTS: The Dementia Assessment Sheet for the Community-based Integrated Care System total score had an area under the curve of 0.831 (95% confidence interval, 0.694-0.914), which was statistically equivalent to performance status. The discriminatory cut-off value for identification of best supportive care was set at 29 with a sensitivity and specificity of 0.742 and 0.897, respectively. Dementia Assessment Sheet for the Community-based Integrated Care System total score showed good concordance with performance status especially when reported by family members or caregivers. Deficits other than activities of daily living were recognized (2.8-19.4%) in patients with good performance status. Impairments were more frequently detected when reported by family members or caregivers. CONCLUSIONS: The Dementia Assessment Sheet for the Community-based Integrated Care System discriminates the best supportive care for older patients with inoperable advanced non-small cell lung cancer. Moreover, it can identify vulnerabilities especially when reported by family members or caregivers that cannot be detected by performance status.

Myeloperoxidase anti-neutrophil cytoplasmic antibody-associated vasculitis with a unique imaging presentation of organizing pneumonia: A case report.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitutes a group of blood vessel inflammation diseases of autoimmune origin. Myeloperoxidase (MPO) ANCA is closely related to ANCA associated AAV. The MPO-ANCA positive AAV patients have lung involvement at high rates; however, there are only a few reported cases with organizing pneumonia (OP). A 78-year-old man was presented to our hospital due to a fever of 38 °C despite a whole month of antibiotics treatment. Chest computed tomography image revealed restricted consolidations visible in the middle lobe of the right lung and the upper lobe of the left lung, which suggested an OP pattern. MPO-ANCA and urine occult blood tests were positive. Histopathological examination of the transbronchial biopsy revealed OP and mucus plug. Histological findings on renal biopsy showed necrotizing glomerulonephritis related to AAV. The patient was diagnosed with MPO-ANCA positive AAV and was treated with systemic corticosteroid therapy, from which he recovered rapidly. Thus, when diagnosing OP, the possibility of AAV should be considered by ordering patients' serum ANCA and occult hematuria tests.

[An elderly case of squamous cell lung cancer treated continuously with pembrolizumab without any decline in the life function].

BACKGROUND: Whether or not immune checkpoint inhibitors are safe and effective for the elderly remains unclear, even though these drugs were approved two years ago for the treatment of advanced non-small cell lung cancer in Japan. Older cancer patients are vulnerable to chemotherapy, so their life function should be closely monitored before starting, continuing, or discontinuing cancer treatment. CASE: An 85-year-old man showed a wedge-shaped shadow in the apical portion of the left lung on chest computed tomography. Unfortunately, repeated bronchoscopy revealed no malignancy. The shadow progressed over about one year, so a third bronchoscopy was performed, leading to a diagnosis of squamous-cell carcinoma (cT3N2M1a, stage IVA). Because PD-L1 immunohistochemical staining was positive for 80%-90% of the tumor cells, the patient was treated with pembrolizumab as the first-line therapy, and the tumor dramatically regressed, notably without any decline in the patient's life functions. CONCLUSION: An elderly case of squamous-cell lung cancer was treated continuously with pembrolizumab without any decline in the patient's life function.