Inhibition of nuclear translocation of NF-kappaB by IkappaBalpha phosphorylation blockade could provide an effective approach to attenuation of ischemia/reperfusion injury. The cardioprotective effects of IMD-0354 include not only reduction of harmful neutrophil accumulation in myocardium but also inhibition of harmful cytokine and chemokine production by cardiomyocytes.

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August 18, 2006; doi:10.1152/ajpheart.00549.2006.-Several studies have demonstrated that NF-B is substantially involved in the progression of cardiac remodeling; however, it remains uncertain whether the continuous inhibition of NF-B is effective for the prevention of myocardial remodeling. Myocardial infarction (MI) was produced by ligation of the left anterior coronary artery of rats. IMD-0354 (10 mg/kg per day), a novel phosphorylation inhibitor of I B that acts via inhibition of IKK-␤, was injected intraperitoneally starting 24 h after induction of MI for 28 days. After 28 days, the IMD-0354-treated group showed significantly improved survival rate compared with that of the vehicle-treated group (P Ͻ 0.05). Although infarct size was similar in both groups, improved left ventricular (LV) remodeling and diastolic dysfunction, as indicated by smaller LV cavity (LV enddiastolic area: vehicle, 74.13 Ϯ 3.57 mm 2 ; IMD-0354, 55.00 Ϯ 3.73 mm 2 ; P Ͻ 0.05), smaller peak velocity of early-to-late filling wave (E/A) ratio (vehicle, 3.87 Ϯ 0.26; IMD-0354, 2.61 Ϯ 0.24; P Ͻ 0.05), and lower plasma brain natriuretic peptide level (vehicle, 167.63 Ϯ 14.87 pg/ml; IMD-0354, 110.75 Ϯ 6.41 pg/ml; P Ͻ 0.05), were observed in the IMD-0354-treated group. Moreover, fibrosis, accumulation of macrophages, and expression of several factors (transforming growth factor-␤1, monocyte chemoattractant protein-1, matrix metalloproteinase-9 and -2) in the noninfarcted myocardium was remarkably inhibited by IMD-0354. In conclusion, inhibition of NF-B activation may reduce the proinflammatory reactions and modulate the extracellular matrix and provide an effective approach to prevent adverse cardiac remodeling after MI. experimental heart failure; nuclear factor-b; matrix metalloproteinase; echocardiography MYOCARDIAL INFARCTION (MI) frequently leads to left ventricular (LV) dilatation and associated interstitial fibrosis in the noninfarcted myocardium. This adverse LV remodeling causes depressed cardiac performance and is an independent determinant of morbidity and mortality after MI (20). One of the recent conceptual advances in our understanding of the pathogenesis of LV remodeling is that this process is driven by the overexpression of various factors, including proinflammatory cytokines, angiotensin II, and norepinephrine, which have direct pathophysiological effects on cardiac myocytes, noncardiac myocytes, and the extracellular matrix (20). Although the expression of proinflammatory cytokines may be involved in wound healing after MI, it is believed that the overexpression of cytokines damages cardiac tissue and evokes excess deposition of fibrotic components, even in the noninfarcted myocardium.Several recent studies reported that nuclear factor-B (NF-B) is involved in the pathogenesis of heart failure (7, 35). Activation of NF-B induces activation of genetic programs that lead to transactivation of cytokines, chemokines, and matrix metalloproteinases (MMPs), promoting inflammatory and fibrotic responses that participate in the progre...

Background-Programmed death-1 (PD-1), a member of the CD28 family, has been identified. PD-1 is involved in the negative regulation of some immune responses. We evaluated the role of PD-ligand 1 (PD-L1) in graft arterial disease (GAD) of cardiac allografts and in smooth muscle cells (SMCs). Methods and Results-C57BL/6 murine hearts were transplanted into B6.C-H2Ͻbm12ϾKhEg mice for examination of GAD. PD-L1 was expressed in SMCs of the thickened intima in the graft coronary arteries, and administration of anti-PD-L1 monoclonal antibody (mAb) enhanced the progression of GAD (luminal occlusion: 55Ϯ5.0% versus 9.8Ϯ4.3%, PϽ0.05). The expressions of interferon ␥ (IFN-␥) and tumor necrosis factor ␣ of cardiac allografts were upregulated in response to anti-PD-L1 mAb treatment. In vitro, PD-L1 expression was induced in SMCs in response to IFN-␥ stimulation. Sensitized splenocytes increased SMC proliferation, and anti-PD-L1 mAb in combination with IFN-␥ stimulation increased this proliferation. Key Words: transplantation Ⅲ graft arterial disease Ⅲ smooth muscle cell Ⅲ immune system Ⅲ B7 family C ardiac allograft transplantation developed as a therapy for end-stage congestive heart failure. The survival rate at 1 year after transplantation has increased to Ͼ80% by introduction of immunosuppressive drugs. 1 However, the use of the drugs also results in opportunistic infection, and these drugs do not prevent graft arterial disease (GAD), which occurs in chronic rejection. Conclusions-TheProgrammed death-1 (PD-1) is a member of the CD28 family that was identified in a T cell line undergoing programmed cell death, 2 but subsequent studies have shown that its expression is associated with lymphocyte activation rather than cell death. 3,4 PD-1 contains an immunoreceptor tyrosine-based inhibitory motif in its cytoplasmic tail. 5 C57BL/6 mice lacking PD-1 develop lupus-like arthritis and glomerulonephritis, 6 and Balb/c mice lacking PD-1 develop fatal dilated cardiomyopathy. 7 Okazaki et al purified the 30-kDa protein from heart extract and identified it as cardiac troponin I in these dilated cardiomyopathy mice, and administration of anti-cardiac troponin I (anti-cTnI) antibody induced heart dilation and dysfunction in wild-type mice. 8 The data suggest that PD-1 receptor engagement leads to downregulation of immune responses. Furthermore, PDligand 1 (PD-L1) was recently identified. 9 PD-1 ligand shows a tissue distribution profile distinct from that of the other B7 family members. Expression of PD-L1 is upregulated on activation of antigen presenting cells, including dendritic cells, monocytes, and B cells. In addition, PD-L1 has been detected in lymphoid as well as in nonlymphoid organs. 10,11 Although Ozkaynak et al reported the expressions and functional roles of PD-1 and PD-L1 in the pathogenesis of cardiac transplants, 12 the relation between the PD-1/PD-L1 pathway and the proliferation of smooth muscle cells (SMCs) has not been investigated. In the present study, we examined the expression of PD-1 and PD-L1 in relation to...

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The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J‐SSCG 2020), a Japanese‐specific set of clinical practice guidelines for sepsis and septic shock created as revised from J‐SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English‐language version of these guidelines was created based on the contents of the original Japanese‐language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high‐quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J‐SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU‐acquired weakness [ICU‐AW], post‐intensive care syndrome [PICS], and body temperature management). The J‐SSCG 2020 covered a total of 22 areas with four additional new areas (patient‐ and family‐centered care, sepsis treatment system, neuro‐intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large‐scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members. As a result, 79 GRADE‐based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J‐SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.

We speculate that the positive-feedback loop (Erk1/2-NF-kB-MCP-1-Erk1/2) is associated with progression of PAH by causing FGF₂-induced inflammation in MCT rats. IMD-0354 has potential as a new therapeutic tool for PAH.

The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2020 (J-SSCG 2020), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created as revised from J-SSCG 2016 jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in September 2020 and published in February 2021. An English-language version of these guidelines was created based on the contents of the original Japanese-language version. The purpose of this guideline is to assist medical staff in making appropriate decisions to improve the prognosis of patients undergoing treatment for sepsis and septic shock. We aimed to provide high-quality guidelines that are easy to use and understand for specialists, general clinicians, and multidisciplinary medical professionals. J-SSCG 2016 took up new subjects that were not present in SSCG 2016 (e.g., ICU-acquired weakness [ICU-AW], post-intensive care syndrome [PICS], and body temperature management). The J-SSCG 2020 covered a total of 22 areas with four additional new areas (patient- and family-centered care, sepsis treatment system, neuro-intensive treatment, and stress ulcers). A total of 118 important clinical issues (clinical questions, CQs) were extracted regardless of the presence or absence of evidence. These CQs also include those that have been given particular focus within Japan. This is a large-scale guideline covering multiple fields; thus, in addition to the 25 committee members, we had the participation and support of a total of 226 members who are professionals (physicians, nurses, physiotherapists, clinical engineers, and pharmacists) and medical workers with a history of sepsis or critical illness. The GRADE method was adopted for making recommendations, and the modified Delphi method was used to determine recommendations by voting from all committee members.As a result, 79 GRADE-based recommendations, 5 Good Practice Statements (GPS), 18 expert consensuses, 27 answers to background questions (BQs), and summaries of definitions and diagnosis of sepsis were created as responses to 118 CQs. We also incorporated visual information for each CQ according to the time course of treatment, and we will also distribute this as an app. The J-SSCG 2020 is expected to be widely used as a useful bedside guideline in the field of sepsis treatment both in Japan and overseas involving multiple disciplines.