Treatment with antifibrotic agents in idiopathic pleuroparenchymal fibroelastosis with usual interstitial pneumonia.

BACKGROUND: There are no established therapeutic options available for idiopathic pleuroparenchymal fibroelastosis (IPPFE) apart from supportive care and lung transplantation. Furthermore, it is known that IPPFE with a usual interstitial pneumonia (UIP) pattern and lower lobe predominance is a disease entity distinct from idiopathic pulmonary fibrosis (IPF). To our knowledge, few studies are available that report on the efficacy of antifibrotic agents for IPPFE with UIP. AIM: The aim of this study was to compare the efficacy of antifibrotic agents between IPPFE with UIP and typical IPF in real-world clinical practice. PATIENTS AND METHODS: A retrospective analysis was performed on the medical records of all patients at two interstitial lung disease centres. Sixty-four patients were diagnosed as having IPPFE with UIP and 195 patients were diagnosed with typical IPF. We compared the efficacy of antifibrotic agents between these two groups. RESULTS: Survival time was significantly shorter in the patients with IPPFE with UIP. Some 125 patients were administered antifibrotic agents for over 6 months (34 with IPPFE with UIP and 91 with typical IPF). Reduced forced vital capacity (FVC) 6 months after treatment with antifibrotic agents was significantly greater in the IPPFE with UIP group than in those in the typical IPF group. Moreover, the change in % predicted FVC was significantly greater during the follow-up in patients with IPPFE with UIP compared with those with typical IPF. CONCLUSIONS: The efficacy of antifibrotic agents was limited in patients with IPPFE with UIP. Thus, IPPFE with UIP remains a fatal and progressive disease.

Lack of whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (WFDC2) causes neonatal death from respiratory failure in mice.

Respiratory failure is a life-threatening problem for pre-term and term infants, yet many causes remain unknown. Here, we present evidence that whey acidic protein (WAP) four-disulfide core domain protease inhibitor 2 (Wfdc2), a protease inhibitor previously unrecognized in respiratory disease, may be a causal factor in infant respiratory failure. Wfdc2 transcripts are detected in the embryonic lung and analysis of a Wfdc2-GFP knock-in mouse line shows that both basal and club cells, and type II alveolar epithelial cells (AECIIs), express Wfdc2 neonatally. Wfdc2-null-mutant mice display progressive atelectasis after birth with a lethal phenotype. Mutant lungs have multiple defects, including impaired cilia and the absence of mature club cells from the tracheo-bronchial airways, and malformed lamellar bodies in AECIIs. RNA sequencing shows significant activation of a pro-inflammatory pathway, but with low-quantity infiltration of mononuclear cells in the lung. These data demonstrate that Wfdc2 function is vitally important for lung aeration at birth and that gene deficiency likely causes failure of the lung mucosal barrier.

A murine model of acute lung injury identifies growth factors to promote tissue repair and their biomarkers.

Type II alveolar epithelial cells (AEC2s) play a crucial role in the regeneration of type I AECs after acute lung injury. The mechanisms underlying the regeneration of AEC2s are not fully understood. To address this issue, here, we investigated a murine model of acute lung injury using mice expressing human Diphtheria Toxin Receptor (DTR) under the control of Lysozyme M promoter (LysM-DTR). DT injection induced the depletion of AEC2s, alveolar macrophages, and bone marrow (BM)-derived myeloid cells in LysM-DTR mice, and the mice died within 6 days after DT injection. Apoptotic AEC2s and bronchiolar epithelial cells appeared at 24 hr, whereas Ki67-positive proliferating cells appeared in the alveoli and bronchioles in the lung of LysM-DTR mice at 72-96 hr after DT injection. Transfer of wild-type BM cells into LysM-DTR mice accelerated the regeneration of AEC2s along with the up-regulation of several growth factors. Moreover, several metabolites were significantly decreased in the sera of LysM-DTR mice compared with WT mice after DT injection, suggesting that these metabolites might be biomarkers to predict AEC2s injury. Together, LysM-DTR mice might be useful to identify growth factors to promote lung repair and the metabolites to predict the severity of lung injury.

Depletion of myeloid cells exacerbates hepatitis and induces an aberrant increase in histone H3 in mouse serum.

Tissue-resident macrophages and bone marrow (BM)-derived monocytes play a crucial role in the maintenance of tissue homeostasis; however, their contribution to recovery from acute tissue injury is not fully understood. To address this issue, we generated an acute murine liver injury model using hepatocyte-specific Cflar-deficient (CflarHep-low ) mice. Cellular FLICE-inhibitory protein expression was down-regulated in Cflar-deficient hepatocytes, which thereby increased susceptibility of hepatocytes to death receptor-induced apoptosis. CflarHep-low mice developed acute hepatitis and recovered with clearance of apoptotic hepatocytes at 24 hours after injection of low doses of tumor necrosis factor α (TNFα), which could not induce hepatitis in wild-type (WT) mice. Depletion of Kupffer cells (KCs) by clodronate liposomes did not impair clearance of dying hepatocytes or exacerbate hepatitis in CflarHep-low mice. To elucidate the roles of BM-derived monocytes and neutrophils in clearance of apoptotic hepatocytes, we examined the effect of depletion of these cells on TNFα-induced hepatitis in CflarHep-low mice. We reconstituted CflarHep-low mice with BM cells from transgenic mice in which human diphtheria toxin receptor (DTR) was expressed under control of the lysozyme M (LysM) promoter. TNFα-induced infiltration of myeloid cells, including monocytes and neutrophils, was completely ablated in LysM-DTR BM-reconstituted CflarHep-low mice pretreated with diphtheria toxin, whereas KCs remained present in the livers. Under these experimental conditions, LysM-DTR BM-reconstituted CflarHep-low mice rapidly developed severe hepatitis and succumbed within several hours of TNFα injection. We found that serum interleukin-6 (IL-6), TNFα, and histone H3 were aberrantly increased in LysM-DTR BM-reconstituted, but not in WT BM-reconstituted, CflarHep-low mice following TNFα injection. CONCLUSION: These findings indicate an unexpected role of myeloid cells in decreasing serum IL-6, TNFα, and histone H3 levels via the suppression of TNFα-induced hepatocyte apoptosis. (Hepatology 2017;65:237-252).

Primary malignant pericardial mesothelioma with increased serum mesothelin diagnosed by surgical pericardial resection: A case report.

A 37-year-old female smoker without a history of exposure to asbestos was referred to our hospital with persistent pericardial effusion. Chest computed tomography imaging examination revealed an irregular thickened pericardium with large amounts of pericardial effusion and a small pleural effusion. Fluorodeoxyglucose (FDG) positron emission tomography imaging demonstrated intrapericardial FDG accumulation. Blood tests revealed an increase in serum mesothelin levels. Examination of a surgically resected specimen revealed a grayish-white thickening of the pericardium, with a straw-colored mucinous pericardial effusion. Histopathological examination confirmed the diagnosis of epithelioid malignant mesothelioma. Although the patient's condition temporarily improved, with decreased levels of serum mesothelin during chemotherapy with carboplatin and pemetrexed, she succumbed to cardiac tamponade 18 months after the initial onset of the symptoms. Primary malignant pericardial mesothelioma (PMPM) is an extremely rare and refractory disorder. Thus, an early definitive diagnosis and timely treatment are crucial for the management of PMPM.