Takefumi Nikaido

Solitary fibrous tumors (SFTs) are rare, spindle-cell neoplasms generally associated with the serosal surface, especially the pleura. Histopathologic, immunohistochemical, ultrastructural, and flow cytometric analyses were performed on seven SFTs of extrapleural sites (two retroperitoneal, two soft tissue, one each peritoneal, nasal cavity, and orbit). Five patients were women, and two were men, aged from 21 to 68 years (average, 39 yr). All of the lesions presented as well-circumscribed masses. The lesions ranged in size from 2 to 20 cm in greatest diameter. Histologically, these lesions were entirely comparable to the pleural SFTs and lacked the characteristic features of other recognized neoplasms that occur in these regions. One tumor contained pleomorphic and round-cell sarcomatous foci. Immunohistochemically, all of the tumors were strongly positive for vimentin and CD34. Six of the seven tumors showed varying numbers of spindle cells positive for alpha smooth muscle actin, HHF35, neuron-specific enolase, Leu 7, or glial fibrillary acidic protein. Ultrastructural examinations of three tumors showed that they were composed of primitive mesenchymal or fibroblast-like cells. Six tumors examined were diploid by flow cytometric examination. Clinical follow-up in six patients ranged from 1 to 7.5 years (average, 2.6 yr) and showed that five patients remained well with no evidence of disease after excision and that the patient with the sarcomatous elements died of recurrence 2.5 years after surgical treatment. These findings suggest that SFTs represent ubiquitous neoplasms of fibroblasts or primitive mesenchymal cells with aggressive potential.

Proteoglycans (PGs) and their associated glycosaminoglycan side chains are effectors of inflammation, but little is known about changes to the composition of PGs in response to lung infection or injury. The goals of this study were to identify changes to heparan sulfate PGs in a mouse model of gram-negative pneumonia, to identify the Toll-like receptor adaptor molecules responsible for these changes, and to determine the role of the heparan sulfate PG in the innate immune response in the lungs. We treated mice with intratracheal LPS, a component of the cell wall of gram-negative bacteria, to model gram-negative pneumonia. Mice treated with intratracheal LPS had a rapid and selective increase in syndecan-4 mRNA that was regulated through MyD88-dependent mechanisms, whereas expression of several other PGs was not affected. To determine the role of syndecan-4 in the inflammatory response, we exposed mice deficient in syndecan-4 to LPS and found a significant increase in neutrophil numbers and amounts of CXC-chemokines and total protein in bronchoalveolar lavage fluid. In studies performed in vitro, macrophages and epithelial cells treated with LPS had increased expression of syndecan-4. Studies performed using BEAS-2B cells showed that pretreatment with heparin and syndecan-4 decreased the expression of CXCL8 mRNA in response to LPS and TNF-α. These findings indicate that the early inflammatory response to LPS involves marked up-regulation of syndecan-4, which functions to limit the extent of pulmonary inflammation and lung injury.

Objective Since the term "combined pulmonary fibrosis and emphysema" (CPFE) was first proposed, the co-existence of pulmonary fibrosis and pulmonary emphysema (PE) has drawn considerable attention. However, conflicting results on the clinical characteristics of patients with both pulmonary fibrosis and PE have been published because of the lack of an exact definition of CPFE. The goal of this study was thus to clarify the clinical characteristics and phenotypes of idiopathic interstitial pneumonia (IIP) with PE. Methods We retrospectively analyzed IIP patients who had been admitted to our hospital. Their chest high-resolution computed tomography images were classified into two groups according to the presence of PE. We then performed a cluster analysis to identify the phenotypes of IIP patients with PE. Results Forty-four (53.7%) out of 82 patients had at least mild emphysema in their bilateral lungs. The cluster analysis separated the IIP patients with PE into three clusters. The overall survival rate of one cluster that consisted of mainly idiopathic pulmonary fibrosis (IPF) patients was significantly worse than those of the other clusters. Conclusion Three different phenotypes can be identified in IIP patients with PE, and IPF with PE is a distinct clinical phenotype with a poor prognosis.

Abstract Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6–7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10 −12 ). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10 −12 ), followed by an additional independent risk allele at HLA-DPβ1 amino acid position 8 (OR = 0.28; P = 3.4 × 10 −7 ). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (β = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.