Yohei Hirano

The absence of typical pneumonia symptoms in a patient with rheumatoid arthritis during tocilizumab and steroid treatment

A 78-year-old woman with rheumatoid arthritis while being treated with tocilizumab and steroid treatment presented with pharyngeal pain and general malaise. She felt chills and vomited while waiting in the waiting room, in addition to urinary incontinence. An immediate evaluation of her condition indicated that she was in shock and a physical examination revealed moist rales in the right lung field. Her white cell count and C reactive protein level were within normal limits; however, a radiological study indicated pneumonia. Antibiotic treatment resulted in improvement of her condition. Blood culture later revealed bacteraemia due to Streptococcus pneumoniae. The anti-inflammatory effect of tocilizumab and steroid treatment may mask the typical symptoms and signs of infection, so physicians must be aware of the potential for hidden infection when such patients present with an unidentified complaint.

Neutralization of Osteopontin Ameliorates Acute Lung Injury Induced by Intestinal Ischemia-reperfusion

Abstract Intestinal ischemia-reperfusion (I/R) is associated with acute respiratory distress syndrome. Osteopontin (OPN), a glycoprotein secreted from immune-reactive cells, plays a deleterious role in various inflammatory diseases. Considering OPN as a pro-inflammatory molecule, we hypothesize that the treatment with its neutralizing antibody (anti-OPN Ab) protects mice against intestinal I/R-induced acute lung injury (ALI). Intestinal I/R was induced in mice by superior mesenteric artery occlusion with a vascular clip. After 45 min of occlusion, the clip was removed and anti-OPN Ab (25 &mgr;g/mouse) or normal IgG isotype control (25 &mgr;g/mouse) was immediately administrated intravenously. Blood, small intestine, and lung tissues were collected at 4 h after reperfusion for various analyses. After intestinal I/R, mRNA and protein levels of OPN were significantly induced in the small intestine, lungs, and blood relative to sham-operated animals. Compared with the IgG control group, treatment of anti-OPN Ab significantly reduced plasma levels of pro-inflammatory cytokine and chemokine (IL-6 and MIP-2) and organ injury markers (AST, ALT, and LDH). The histological architecture of the gut and lung tissues in anti-OPN Ab-treated intestinal I/R-induced mice showed significant improvement versus the IgG control mice. The lung inflammation measured by the levels of IL-6, IL-1&bgr;, and MIP-2 was also significantly downregulated in the anti-OPN Ab-treated mice as compared with the IgG control mice. Besides, the lung MPO and neutrophil infiltration in anti-OPN Ab-treated mice showed significant reduction as compared with the IgG control animals. In conclusion, we have demonstrated beneficial outcomes of anti-OPN Ab treatment in protecting against ALI, implicating a novel therapeutic potential in intestinal I/R.

Role of reverse transendothelial migration of neutrophils in inflammation.

Abstract Transmigration of neutrophils through vascular endothelial walls into the inflamed tissues is a critical defense mechanism of innate immune system against infection and injury caused by sepsis, trauma, ischemia-reperfusion, and other acute or chronic inflammatory diseases. However, their excessive infiltration and uncontrolled activation may lead to the destruction of normal tissue architecture and unrestrained inflammation. Transendothelial migration (TEM) in a luminal-to-abluminal direction is widely known as the final step of neutrophil migration cascade into the inflamed tissues. Recent studies have shown that neutrophils not necessarily move from the vascular lumen to the extravascular tissues in a one way direction; they also proceed in an opposite direction, known as reverse transendothelial migration (rTEM) to get back into the vascular lumen again. This novel paradigm of neutrophil round trip is currently on the spotlight due to its possible interaction with immune system. Current review highlighting the growing demand of this newly identified neutrophil migratory event will not only rewrite the disease pathophysiology, but also help scientists design novel therapeutic strategy leading to the remission of inflammatory diseases in which controlling exaggerated neutrophil infiltration is a major challenge.

MFG‐E8‐derived peptide attenuates adhesion and migration of immune cells to endothelial cells

Milk fat globule‐epidermal growth factor‐factor 8 (MFG‐E8) plays an immunomodulatory role in inflammatory diseases. MFG‐E8‐derived short peptide (MSP68) greatly reduces neutrophil infiltration and injury in the lung during sepsis. In this study, we examined the effect of MSP68 on chemotaxis of various immune cells and its regulatory mechanism. Bone marrow‐derived neutrophils (BMDNs) from C57BL/6 mice, human monocyte THP‐1 cell line, and human T lymphocyte Jurkat cell line were used for adhesion and migration assays using a Transwell method in the presence of MSP68. Treatment with MSP68 significantly inhibited the BMDN and THP‐1 cell but not Jurkat cell adhesion on the TNF‐α‐stimulated pulmonary artery endothelial cell (PAEC) monolayer dose‐dependently. MSP68 also significantly reduced BMDN adhesion on VCAM‐1‐coated wells dose dependently. Surface plasmon resonance (SPR) analysis revealed that MSP68 efficiently recognized integrin α4β1 (receptor for VCAM‐1) at the dissociation constant (KD) of 1.53 × 10−7 M. These findings implicate that MSP68 prevents neutrophil adhesion to the activated endothelial cells by interfering with the binding between integrin α4β1 on neutrophils and VCAM‐1 on endothelial cells. Moreover, MSP68 significantly attenuated the migration of BMDN and THP‐1 cells but not Jurkat cells to their chemoattractants. Pretreatment with MSP68 inhibited the transmigration of BMDNs across the PAECs toward chemoattractants, fMLP, MIP‐2, and complement fragment 5a (C5a) dose‐dependently. Finally, we identified that the activation of p38 MAPK in BMDNs by fMLP was inhibited by MSP68. Thus, MSP68 attenuates extravasation of immune cells through the endothelial cell lining into inflamed tissue, implicating MSP68 to be a novel, therapeutic agent for inflammatory diseases caused by excessive immune cell infiltration.

A case of emphysematous pyelonephritis induced by Citrobacter freundii infection

A 79-year-old female with diabetes mellitus had general fatigue, a high fever and vomiting. A CT revealed acute emphysematous pyelonephritis (EPN). A nephrectomy was performed on the 2nd hospital day. The results of the blood culture showed the presence of Citrobacter freundii infection. The patients post-operative course was uneventful. This case is the second reported case of EPN induced by Citrobacter freundii. Bacteremia induced by Citrobacter freundii infection typically results in a high mortality rate. In this case, the early diagnosis of the EPN using CT and immediate medical treatment, including urgent elective nephrectomy, were key to the favorable outcome.

Targeting junctional adhesion molecule‐C ameliorates sepsis‐induced acute lung injury by decreasing CXCR4+ aged neutrophils

Sepsis is a severe inflammatory condition associated with high mortality. Transmigration of neutrophils into tissues increases their lifespan to promote deleterious function. Junctional adhesion molecule‐C (JAM‐C) plays a pivotal role in neutrophil transmigration into tissues. We aim to study the role of JAM‐C on the aging of neutrophils to cause sepsis‐induced acute lung injury (ALI). Sepsis was induced in C57BL/6J mice by cecal ligation and puncture (CLP) and JAM‐C expression in serum was assessed. Bone marrow‐derived neutrophils (BMDN) were treated with recombinant mouse JAM‐C (rmJAM‐C) ex vivo and their viability was assessed. CLP‐operated animals were administrated with either isotype IgG or anti‐JAM‐C Ab at a concentration of 3 mg/kg and after 20 h, aged neutrophils (CXCR4+) were assessed in blood and lungs and correlated with systemic injury and inflammatory markers. Soluble JAM‐C level in serum was up‐regulated during sepsis. Treatment with rmJAM‐C inhibited BMDN apoptosis, thereby increasing their lifespan. CLP increased the frequencies of CXCR4+ neutrophils in blood and lungs, while treatment with anti‐JAM‐C Ab significantly reduced the frequencies of CXCR4+ aged neutrophils. Treatment with anti‐JAM‐C Ab significantly reduced systemic injury markers (alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) as well as systemic and lung inflammatory cytokines (IL‐6 and IL‐1β) and chemokine (macrophage inflammatory protein‐2). The blockade of JAM‐C improved lung histology and reduced neutrophil contents in lungs of septic mice. Thus, reduction of the pro‐inflammatory aged neutrophils by blockade of JAM‐C has a novel therapeutic potential in sepsis‐induced ALI.