Role of microbiota-derived corisin in coagulation activation during SARS-CoV-2 infection.

BACKGROUND: Coagulopathy is a major cause of morbidity and mortality in COVID-19 patients. Hypercoagulability in COVID-19 results in deep vein thrombosis, thromboembolic complications, and diffuse intravascular coagulation. Microbiome dysbiosis influences the clinical course of COVID-19. However, the role of dysbiosis in COVID-19-associated coagulopathy is not fully understood. OBJECTIVES: The present study tested the hypothesis that the microbiota-derived proapoptotic corisin is involved in the coagulation system activation during SARS-CoV-2 infection. METHODS: This cross-sectional study included 47 consecutive patients who consulted for symptoms of COVID-19. A mouse acute lung injury model was used to recapitulate the clinical findings. A549 alveolar epithelial, THP-1, and human umbilical vein endothelial cells were used to evaluate procoagulant and anticoagulant activity of corisin. RESULTS: COVID-19 patients showed significantly high circulating levels of corisin, thrombin-antithrombin complex, D-dimer, tumor necrosis factor-α, and monocyte-chemoattractant protein-1 with reduced levels of free protein S compared with healthy subjects. The levels of thrombin-antithrombin complex, D-dimer, and corisin were significantly correlated. A monoclonal anticorisin-neutralizing antibody significantly inhibited the inflammatory response and coagulation system activation in a SARS-CoV-2 spike protein-associated acute lung injury mouse model, and the levels of corisin and thrombin-antithrombin complex were significantly correlated. In an in vitro experiment, corisin increased the tissue factor activity and decreased the anticoagulant activity of thrombomodulin in epithelial, endothelial, and monocytic cells. CONCLUSION: The microbiota-derived corisin is significantly increased and correlated with activation of the coagulation system during SARS-CoV-2 infection, and corisin may directly increase the procoagulant activity in epithelial, endothelial, and monocytic cells.

Bilateral Nephrectomy for Resistant Hypertension and Secondary Aldosteronism in a Hemodialysis Patient: A Case Report.

A 42-year-old Japanese woman with end-stage renal failure due to hypertension presented with a systolic blood pressure of 160-200 mmHg despite treatment with 4 different antihypertensive agents. The plasma aldosterone concentration (PAC) and plasma renin activity (PRA) were elevated. Adrenal vein sampling suggested bilateral excessive aldosterone secretion, whereas adrenocortical scintigraphy showed right-dominant accumulation. Open bilateral nephrectomy and right adrenalectomy improved the systolic blood pressure, PAC, and PRA. A pathological examination revealed zona glomerulosa hyperplasia but not microaldosteronoma. This report shows that bilateral nephrectomy, not unilateral adrenalectomy, is a potentially effective treatment option for resistant hypertension with an elevated renin-angiotensin-aldosterone system in hemodialysis patients.

Amelioration of Pulmonary Fibrosis by Matrix Metalloproteinase-2 Overexpression.

Idiopathic pulmonary fibrosis is a progressive and fatal disease with a poor prognosis. Matrix metalloproteinase-2 is involved in the pathogenesis of organ fibrosis. The role of matrix metalloproteinase-2 in lung fibrosis is unclear. This study evaluated whether overexpression of matrix metalloproteinase-2 affects the development of pulmonary fibrosis. Lung fibrosis was induced by bleomycin in wild-type mice and transgenic mice overexpressing human matrix metalloproteinase-2. Mice expressing human matrix metalloproteinase-2 showed significantly decreased infiltration of inflammatory cells and inflammatory and fibrotic cytokines in the lungs compared to wild-type mice after induction of lung injury and fibrosis with bleomycin. The computed tomography score, Ashcroft score of fibrosis, and lung collagen deposition were significantly reduced in human matrix metalloproteinase transgenic mice compared to wild-type mice. The expression of anti-apoptotic genes was significantly increased, while caspase-3 activity was significantly reduced in the lungs of matrix metalloproteinase-2 transgenic mice compared to wild-type mice. Active matrix metalloproteinase-2 significantly decreased bleomycin-induced apoptosis in alveolar epithelial cells. Matrix metalloproteinase-2 appears to protect against pulmonary fibrosis by inhibiting apoptosis of lung epithelial cells.

Inhibition of a Microbiota-Derived Peptide Ameliorates Established Acute Lung Injury.

Acute lung injury (ALI) is a clinical syndrome characterized by a diffuse lung inflammation that commonly evolves into acute respiratory distress syndrome and respiratory failure. The lung microbiota is involved in the pathogenesis of ALI. Corisin, a proapoptotic peptide derived from the lung microbiota, plays a role in ALI and acute exacerbation of pulmonary fibrosis. Preventive therapeutic intervention with a monoclonal anticorisin antibody inhibits ALI in mice. However, whether inhibition of corisin with the antibody ameliorates established ALI is unknown. Here, the therapeutic effectiveness of the anticorisin antibody in already established ALI in mice was assessed. Lipopolysaccharide was used to induce ALI in mice. After causing ALI, the mice were treated with a neutralizing anticorisin antibody. Mice treated with the antibody showed significant improvement in lung radiological and histopathologic findings, decreased lung infiltration of inflammatory cells, reduced markers of lung tissue damage, and inflammatory cytokines in bronchoalveolar lavage fluid compared with untreated mice. In addition, the mice treated with anticorisin antibody showed significantly increased expression of antiapoptotic proteins with decreased caspase-3 activation in the lungs compared with control mice treated with an irrelevant antibody. In conclusion, these observations suggest that the inhibition of corisin is a novel and promising approach for treating established ALI.

Transforming Growth Factorß1 Overexpression Is Associated with Insulin Resistance and Rapidly Progressive Kidney Fibrosis under Diabetic Conditions.

Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The role of transforming growth factorß1 in kidney fibrosis is undebatable. This study assessed whether the overexpression of transforming growth factorß1 is associated with insulin resistance and the rapid progression of transforming growth factorß1-mediated nephropathy under diabetic conditions. Diabetes mellitus was induced with streptozotocin in wild-type mice and transgenic mice with the kidney-specific overexpression of human transforming growth factorß1. Mice treated with saline were the controls. Glucose tolerance and kidney fibrosis were evaluated. The blood glucose levels, the values of the homeostasis model assessment for insulin resistance, and the area of kidney fibrosis were significantly increased, and the renal function was significantly impaired in the diabetic transforming growth factorß1 transgenic mice compared to the non-diabetic transgenic mice, diabetic wild-type mice, and non-diabetic mice. Transforming growth factorß1 impaired the regulatory effect of insulin on glucose in the hepatocyte and skeletal muscle cell lines. This study shows that transforming growth factorß1 overexpression is associated with insulin resistance and rapidly progressive kidney fibrosis under diabetic conditions in mice.

Adrenocorticotropic hormone-secreting pancreatic neuroendocrine carcinoma with multiple organ infections and widespread thrombosis: A case report.

BACKGROUND: Ectopic adrenocorticotropic hormone (ACTH)-secreting neuroendocrine tumors are rare diseases. Patients with ACTH-secreting pancreatic neuroendocrine carcinomas have a poor prognosis. Infections and coagulopathies have been reported as the cause of death. However, detailed clinical descriptions of the morbid complications of ACTH-secreting neuroendocrine carcinomas have not been reported. CASE SUMMARY: A 78-year-old Japanese woman consulted a medical center due to systemic edema and epigastric discomfort. Laboratory analysis revealed hypercortisolemia with increased ACTH secretion without diurnal variation in serum cortisol level. An enhanced computed tomography (CT) scan revealed a 3-cm tumor in the pancreatic head. The cytological material from endoscopic ultrasound-guided fine-needle aspiration was compatible with ACTH-secreting pancreatic neuroendocrine carcinoma. The Ki-67 index was 40%. She was transferred to Mie University Hospital for surgical treatment. The patient was diagnosed with urinary tract infection, cytomegalovirus hepatitis, esophageal candidiasis, pulmonary infiltrates suspicious for Pneumocystis carinii pneumonia, peripheral deep vein thrombosis, pulmonary embolism, and disseminated intravascular coagulation. The multiple organ infections and thromboses responded well to antimicrobial and anticoagulant therapy. Radioisotope studies disclosed a pancreatic tumor and a metastatic lesion in the liver, whereas somatostatin receptor scintigraphy showed negative findings, suggesting the primary and metastatic tumors were poorly differentiated. A CT scan before admission showed no metastatic liver lesion, suggesting that the pancreatic tumor was rapidly progressing. Instead of surgery, antitumor chemotherapy was indicated. The patient was transferred to another hospital to initiate chemotherapy. However, she died four months later due to the rapidly progressive tumor. CONCLUSION: ACTH-secreting pancreatic neuroendocrine neoplasm is a rare disease with a very poor prognosis. The clinical course and acute complications of the tumor remain unreported. Here we report the clinical course of a rapidly progressive case of ACTH-secreting pancreatic neuroendocrine tumor that developed infectious complications due to many types of pathogens in multiple organs, widespread thromboses, pulmonary embolism, and disseminated intravascular coagulation.

Inhibition of lung microbiota-derived proapoptotic peptides ameliorates acute exacerbation of pulmonary fibrosis.

Idiopathic pulmonary fibrosis is an incurable disease of unknown etiology. Acute exacerbation of idiopathic pulmonary fibrosis is associated with high mortality. Excessive apoptosis of lung epithelial cells occurs in pulmonary fibrosis acute exacerbation. We recently identified corisin, a proapoptotic peptide that triggers acute exacerbation of pulmonary fibrosis. Here, we provide insights into the mechanism underlying the processing and release of corisin. Furthermore, we demonstrate that an anticorisin monoclonal antibody ameliorates lung fibrosis by significantly inhibiting acute exacerbation in the human transforming growth factorß1 model and acute lung injury in the bleomycin model. By investigating the impact of the anticorisin monoclonal antibody in a general model of acute lung injury, we further unravel the potential of corisin to impact such diseases. These results underscore the role of corisin in the pathogenesis of acute exacerbation of pulmonary fibrosis and acute lung injury and provide a novel approach to treating this incurable disease.

The Fairy Chemical Imidazole-4-carboxamide Inhibits the Expression of Axl, PD-L1, and PD-L2 and Improves Response to Cisplatin in Melanoma.

The leading cause of death worldwide is cancer. Many reports have proved the beneficial effect of mushrooms in cancer. However, the precise mechanism is not completely clear. In the present study, we focused on the medicinal properties of biomolecules released by fairy ring-forming mushrooms. Fairy chemicals generally stimulate or inhibit the growth of surrounding vegetation. In the present study, we evaluated whether fairy chemicals (2-azahypoxanthine, 2-aza-8-oxohypoxanthine, and imidazole-4-carboxamide) exert anticancer activity by decreasing the expression of Axl and immune checkpoint molecules in melanoma cells. We used B16F10 melanoma cell lines and a melanoma xenograft model in the experiments. Treatment of melanoma xenograft with cisplatin combined with imidazole-4-carboxamide significantly decreased the tumor volume compared to untreated mice or mice treated cisplatin alone. In addition, mice treated with cisplatin and imidazole-4-carboxamide showed increased peritumoral infiltration of T cells compared to mice treated with cisplatin alone. In vitro studies showed that all fairy chemicals, including imidazole-4-carboxamide, inhibit the expression of immune checkpoint molecules and Axl compared to controls. Imidazole-4-carboxamide also significantly blocks the cisplatin-induced upregulation of PD-L1. These observations point to the fairy chemical imidazole-4-carboxamide as a promising coadjuvant therapy with cisplatin in patients with cancer.

Case Report: A Difficult-to-Diagnose Case of Hyperinsulinemic Hypoglycemia Surgically Treated After Developing Acute Pancreatitis.

The patient is a 28-year-old Japanese man diagnosed with severe congenital hyperinsulinemic-hypoglycemia six months after birth. Clinical records revealed no imaging evidence of pancreatic tumor at the time of diagnosis. Subsequently, he had developmental disorders and epilepsy caused by recurrent hypoglycemic attacks. The patient's hypoglycemia improved with oral diazoxide. However, he developed necrotizing acute pancreatitis at 28 years of age, thought to be due to diazoxide. Discontinuation of diazoxide caused persistent hypoglycemia, requiring continuous glucose supplementation by tube feeding and total parenteral nutrition. A selective arterial secretagogue injection test revealed diffuse pancreatic hypersecretion of insulin. He underwent subtotal distal (72%) pancreatectomy and splenectomy. There was no intraoperative visible pancreatic tumor. His hypoglycemia improved after the surgical procedure. The histopathological study revealed a high density of islets of Langerhans in the pancreatic body and tail. There were large islets of Langerhans and multiple neuroendocrine cell nests in the whole pancreas. Nests of neuroendocrine cells were also detected in lymph nodes. The pathological diagnosis was grade 1 neuroendocrine tumor (microinsulinomas) with lymph node metastases. This patient is a difficult-to-diagnose case of hyperinsulinemic hypoglycemia surgically treated after developing acute pancreatitis. We believe this is a unique case of microinsulinomas with lymph metastases diagnosed and treated as congenital hyperinsulinemic hypoglycemia for almost 28 years.

Protective Role of Recombinant Human Thrombomodulin in Diabetes Mellitus.

Diabetes mellitus is a global threat to human health. The ultimate cause of diabetes mellitus is insufficient insulin production and secretion associated with reduced pancreatic ß-cell mass. Apoptosis is an important and well-recognized mechanism of the progressive loss of functional ß-cells. However, there are currently no available antiapoptotic drugs for diabetes mellitus. This study evaluated whether recombinant human thrombomodulin can inhibit ß-cell apoptosis and improve glucose intolerance in a diabetes mouse model. A streptozotocin-induced diabetes mouse model was prepared and treated with thrombomodulin or saline three times per week for eight weeks. The glucose tolerance and apoptosis of ß-cells were evaluated. Diabetic mice treated with recombinant human thrombomodulin showed significantly improved glucose tolerance, increased insulin secretion, decreased pancreatic islet areas of apoptotic ß-cells, and enhanced proportion of regulatory T cells and tolerogenic dendritic cells in the spleen compared to counterpart diseased mice treated with saline. Non-diabetic mice showed no changes. This study shows that recombinant human thrombomodulin, a drug currently used to treat patients with coagulopathy in Japan, ameliorates glucose intolerance by protecting pancreatic islet ß-cells from apoptosis and modulating the immune response in diabetic mice. This observation points to recombinant human thrombomodulin as a promising antiapoptotic drug for diabetes mellitus.

Oral Limonite Supplement Ameliorates Glucose Intolerance in Diabetic and Obese Mice.

INTRODUCTION: Diabetes mellitus is a serious threat to public health worldwide. It causes a substantial economic burden, mental and physical disabilities, poor quality of life, and high mortality. Limonite is formed when iron-rich materials from the underground emerge and oxidized on the ground surface. It is currently used to purify contaminated water, absorption of irritant gases, and improve livestock breeding. Limonite can change the composition of environmental microbial communities. In the present study, we evaluated whether limonite can ameliorate glucose metabolism abnormalities by remodeling the gut microbiome. METHODS: The investigation was performed using mouse models of streptozotocin-induced diabetes mellitus and high-calorie diet-induced metabolic syndrome. RESULTS: Oral limonite supplement was associated with significant body weight recovery, reduced glycemia with improved insulin secretion, increased number of regulatory T cells, and abundant beneficial gut microbial populations in mice with diabetes mellitus compared to control. Similarly, mice with obesity fed with limonite supplements had significantly reduced body weight, insulin resistance, steatohepatitis, and systemic inflammatory response with significant gut microbiome remodeling. CONCLUSION: This study demonstrates that limonite supplement ameliorates abnormal glucose metabolism in diabetes mellitus and obesity. Gut microbiome remodeling, inhibition of inflammatory cytokines, and the host immune response regulation may explain the limonite's beneficial activity under pathological conditions in vivo.

Degradation Products of Complex Arabinoxylans by Bacteroides intestinalis Enhance the Host Immune Response.

Bacteroides spp. of the human colonic microbiome degrade complex arabinoxylans from dietary fiber and release ferulic acid. Several studies have demonstrated the beneficial effects of ferulic acid. Here, we hypothesized that ferulic acid or the ferulic acid-rich culture supernatant of Bacteroides intestinalis, cultured in the presence of complex arabinoxylans, enhances the immune response. Ferulic acid and the culture supernatant of bacteria cultured in the presence of insoluble arabinoxylans significantly decreased the expression of tumor necrosis factor-α and increased the expression of interleukin-10 and transforming growth factor ß1 from activated dendritic cells compared to controls. The number of granulocytes in mesenteric lymph nodes, the number of spleen monocytes/granulocytes, and interleukin-2 and interleukin-12 plasma levels were significantly increased in mice treated with ferulic acid or the culture supernatant of bacteria cultured with insoluble arabinoxylans. Ferulic acid or the culture supernatant of bacteria cultured with insoluble arabinoxylans increased the expression of interleukin-12, interferon-α, and interferon-ß in intestinal epithelial cell lines. This study shows that ferulic acid or the ferulic acid-rich culture supernatant of the colonic bacterium Bacteroides intestinalis, cultured with insoluble arabinoxylans, exerts anti-inflammatory activity in dendritic cells under inflammatory conditions and enhances the Th1-type immune response under physiological conditions in mice.

Sodium-glucose co-transporter-2 inhibitor-associated euglycemic diabetic ketoacidosis that prompted the diagnosis of fulminant type-1 diabetes: A case report.

BACKGROUND: Fulminant type 1 diabetes mellitus (FT1DM) is a subtype of type 1 diabetes mellitus characterized by an abrupt onset and a rapid and complete functional loss of islet ß cells. It is a very rare disease generally associated with ketoacidosis and the absence of circulating pancreatic islet-related autoantibodies. Diabetic ketoacidosis with normal blood glucose levels has been reported during sodium-glucose co-transporter 2 (SGLT2) inhibitor therapy. CASE SUMMARY: The patient was a 43-year-old woman that consulted a medical practitioner for malaise, thirst, and vomiting. Blood analysis showed high blood glucose levels (428 mg/dL), a mild increase of hemoglobin A1c (6.6%), and increased ketone bodies in urine. The patient was diagnosed with type 2 diabetes mellitus. The patient was initially treated with insulin, which was subsequently changed to an oral SGLT2 inhibitor. Antibodies to glutamic acid decarboxylase were negative. Four days after receiving oral SGLT2 inhibitor, she consulted at Mie University Hospital, complaining of fatigue and vomiting. Laboratory analysis revealed diabetic ketoacidosis with almost normal blood glucose levels. The endogenous insulin secretion was markedly low, and the serum levels of islet-related autoantibodies were undetectable. We made the diagnosis of FT1DM with concurrent SGLT2 inhibitor-associated euglycemic diabetic ketoacidosis. The patient's general condition improved after therapy with intravenous insulin and withdrawal of oral medication. She was discharged on day 14 with an indication of multiple daily insulin therapy. CONCLUSION: This patient is a rare case of FT1DM that developed SGLT2 inhibitor-associated diabetic ketoacidosis with almost normal blood glucose levels. This case report underscores the importance of considering the diagnosis of FT1DM in patients with negative circulating autoantibodies and a history of hyperglycemia that subsequently develop euglycemic diabetic ketoacidosis following treatment with a SGLT2 inhibitor.

Sudden Death Associated with Severe Hypoglycemia in a Diabetic Patient During Sensor-Augmented Pump Therapy with the Predictive Low Glucose Management System.

BACKGROUND Hypoglycemia is a frequent complication observed in diabetic patients under treatment. This metabolic complication is associated with an increased mortality rate in diabetic patients. The use of sensor-augmented pump therapy with predictive low glucose management systems has improved blood glucose level control and reduced the incidence of hypoglycemic attacks. However, this therapy may be associated with adverse events. CASE REPORT A 65-year-old Japanese woman with type 1 diabetes mellitus underwent hemodialysis with end-stage renal failure due to diabetic nephropathy. The patient received sensor-augmented pump therapy with the predictive low glucose management system to prevent recurrent severe hypoglycemia. Hypoglycemia was infrequent when the sensor-augmented pump therapy with a predictive low-glucose management system was properly working. However, the patient suddenly died 3 months after starting the treatment. A record of continuous glucose monitoring showed that hypoglycemia occurred before the sudden death of the patient. CONCLUSIONS The current case shows that sudden death associated with severe hypoglycemia may also occur during sensor-augmented pump therapy with a predictive low glucose management system. This case report underscores the need for close follow-up of diabetic patients receiving sensor-augmented pump therapy with the predictive low glucose management system and the critical importance of patient education on diabetes technology in high-risk patients.

Missed diagnosis and delayed treatment of acromegaly in a patient with severe diabetes: A case report.

The early stages of acromegaly are characterized by slow and progressive acral overgrowth without major systemic complications. Failure to diagnose acromegaly at an early stage may have devastating consequences on patient care. The case in the present report was a 44-year-old Japanese man, referred to Kuwana City Medical Center due to severe hyperglycemia detected in a general checkup. The patient had no acromegaly-related complaints. Laboratory data revealed high blood levels of hemoglobin A1c and glucose. Careful physical examination revealed enlargement of extremities and soft tissues. Laboratory investigation indicated a high blood concentration of growth hormone, and magnetic resonance imaging disclosed an enhanced pituitary tumor. The diagnosis was pituitary tumor-associated acromegaly with severe diabetic complications. The pituitary tumor became large and unresectable following 10 years of misdiagnosis. The patient was treated with somatostatin receptor ligands (lanreotide and pasireotide), as well as bromocriptine in Mie University Hospital. The tumor size was reduced following treatment, though it was still unresectable at the time of this report. The case highlights the importance of hyperglycemia and abnormal manifestations of the feet in patients with acromegaly. In addition, these findings highlight the need for a thorough examination of the feet in diabetic patients, and the critical importance of the early diagnosis of acromegaly for preventing the consequences of inappropriate patient care.

Thrombomodulin ameliorates transforming growth factor-ß1-mediated chronic kidney disease via the G-protein coupled receptor 15/Akt signal pathway.

Kidney fibrosis is the common consequence of chronic kidney diseases that inexorably progresses to end-stage kidney disease with organ failure treatable only with replacement therapy. Since transforming growth factor-ß1 is the main player in the pathogenesis of kidney fibrosis, we posed the hypothesis that recombinant thrombomodulin can ameliorate transforming growth factor-ß1-mediated progressive kidney fibrosis and failure. To interrogate our hypothesis, we generated a novel glomerulus-specific human transforming growth factor-ß1 transgenic mouse to evaluate the therapeutic effect of recombinant thrombomodulin. This transgenic mouse developed progressive glomerular sclerosis and tubulointerstitial fibrosis with kidney failure. Therapy with recombinant thrombomodulin for four weeks significantly inhibited kidney fibrosis and improved organ function compared to untreated transgenic mice. Treatment with recombinant thrombomodulin significantly inhibited apoptosis and mesenchymal differentiation of podocytes by interacting with the G-protein coupled receptor 15 to activate the Akt signaling pathway and to upregulate the expression of anti-apoptotic proteins including survivin. Thus, our study strongly suggests the potential therapeutic efficacy of recombinant thrombomodulin for the treatment of chronic kidney disease and subsequent organ failure.

De Novo T790M Mutation in an L858R Epidermal Growth Factor Receptor Mutant-Associated Lung Adenocarcinoma.

Background: Lung cancer is the leading cause of mortality for cancer worldwide. A point mutation in exon 21 of the epidermal growth factor receptor resulting in the substitution of arginine for leucine at position 858 (L858R) is a frequent cause of lung adenocarcinoma. Tyrosine kinase inhibitors are effective for treating patients with lung cancer associated with mutant epidermal growth factor receptors but most tumors become resistant shortly after treatment. The substitution of methionine for threonine at position 790 (T790M) on exon 20 is the most frequently acquired mutation leading to resistance to tyrosine kinase inhibitors. Whether the T790M mutation occurred after tyrosine kinase inhibitor therapy or it already existed before therapy is unclear. Methods: Here, we developed mice with tetracycline-inducible lung-specific expression of the full-length genomic DNA of the human epidermal growth factor receptor containing an L858R mutation or both L858R and T790M mutations and evaluated de novo T790M mutation in untreated transgenic mice carrying a single L858R EGFR mutation. Results: The L858R mutation-associated lung adenocarcinoma acquired de novo T790 mutation without previous therapy. Conclusions: The results of this study suggest that lung tumors may spontaneously acquire T790M mutations without any drug-related selective pressure.

A Staphylococcus pro-apoptotic peptide induces acute exacerbation of pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis.

Protein S protects against allergic bronchial asthma by modulating Th1/Th2 balance.

BACKGROUND: Bronchial asthma is a chronic disease characterized by inflammation, obstruction, and hyperresponsiveness of the airways. There is currently no curative therapy for asthma. Type 2 helper T cell response plays a critical role in the pathogenesis of the disease. Protein S is a glycoprotein endowed with anticoagulant, anti-inflammatory, and anti-apoptotic properties. Whether protein S can suppress bronchial asthma and be useful for its therapy is unknown. METHODS: To address this question here we compared the development of allergen-associated bronchial asthma between wild type and protein S-overexpressing transgenic mice. Mice were sensitized and challenged with ovalbumin. We also evaluated the circulating levels of total and active protein S in patients with bronchial asthma and healthy controls. RESULTS: The circulating level of total protein S and of its active form was significantly decreased in patients with bronchial asthma compared to controls. Allergic protein S transgenic mice showed a significant reduction of airway hyperresponsiveness, lung tissue inflammatory cell infiltration, lung levels of Th2 cytokines and IgE compared to their wild-type counterparts. Administration of exogenous human protein S also decreased airway hyperresponsiveness and Th2-mediated lung inflammation in allergic wild-type mice compared with their untreated mouse counterparts. Human protein S significantly shifted the Th1/Th2 balance to Th1 and promoted the secretion of Th1 cytokines (IL-12, tumor necrosis factor-α) from dendritic cells. CONCLUSIONS: These observations suggest the strong protective activity of protein S against the development of allergic bronchial asthma implicating its potential usefulness for the disease treatment.