Surfactant “fortification” by topical inhibition of nuclear factor-κB activity in a newborn piglet lavage model*

Bismarck, Philipp von; Klemm, Karsten; Wistädt, Carlos-Francisco García; Winoto-Morbach, Supandi; Uhlig, Ulrike; Schütze, Stefan; Uhlig, Stefan; Lachmann, Burkhard; Krause, Martín

doi:10.1097/01.ccm.0000281472.47067.45

Cited by 20 publications

(17 citation statements)

References 59 publications

(51 reference statements)

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“…Furthermore, the many separate routes of administration used to deliver the NBD (including i.p., i.v., topical, intranasal, intracranial) demonstrate that it can function systemically and reach distant tissue sites although the precise pharmacokinetics remain to be determined [57]. Finally, several reports have demonstrated that the NBD peptide blocks inXammation in large animal models of disease including a piglet model of acute respiratory distress syndrome [66][67][68]. This therefore supports the exciting promise that this approach holds for possible future translational studies in the clinic.…”

Section: The Nemo Binding Domain Peptidementioning

confidence: 71%

The IκB kinase complex: master regulator of NF-κB signaling

2008

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The Nuclear Factor-kappa B (NF-kappaB) family of transcription factors regulates the expression of a wide range of genes critical for immune and inflammatory responses, cell survival, immune development, and cell proliferation. Dysregulated NF-kappaB activity occurs in a number of chronic inflammatory diseases and certain types of cancers making NF-kappaB signaling an attractive target for the development of anti-inflammatory and anti-cancer drugs. A pivotal regulator of all inducible NF-kappaB signaling pathways is the IkappaB kinase (IKK) complex that consists of two kinases (IKKalpha and IKKbeta) and a regulatory subunit named NF-kappaB essential modulator (NEMO). Genetic analysis of the IKK complex has identified two separate pathways named the classical and non-canonical mechanisms that are dependent on either NEMO and IKKbeta (classical) or IKKalpha alone (non-canonical). To better understand the mechanisms that regulate IKK complex activity and to address the differential functions of IKKalpha and IKKbeta we have molecularly dissected the IKKs. We describe here how these studies have identified a unique inhibitor of pro-inflammatory NF-kappaB signaling, an unforeseen role for IKKalpha in the classical NF-kappaB pathway, and a novel functional domain in IKKbeta that is not present in IKKalpha.

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Section: The Nemo Binding Domain Peptidementioning

confidence: 71%

The IκB kinase complex: master regulator of NF-κB signaling

2008

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“…More recently, Chapoval et al showed that the peptide reduced IL-13-induced tissue inflammation, fibrosis and alveolar remodeling in an IL-13-transgenic mouse model of asthma [168]. In separate studies, topical nasal administration of the NBD peptide in piglets inhibited severe inflammation induced by repeated airway lavage [169, 170]. In this model of acute respiratory distress syndrome the peptide significantly reduced lung edema, protein content in the epithelial lining fluid, PMN accumulation and leukotriene B4 levels and improved the functional residual capacity, alveolar volume and lung mechanics [169, 170].…”

Section: Introductionmentioning

confidence: 99%

“…In separate studies, topical nasal administration of the NBD peptide in piglets inhibited severe inflammation induced by repeated airway lavage [169, 170]. In this model of acute respiratory distress syndrome the peptide significantly reduced lung edema, protein content in the epithelial lining fluid, PMN accumulation and leukotriene B4 levels and improved the functional residual capacity, alveolar volume and lung mechanics [169, 170]. Importantly, in addition to verifying the ability of the NBD peptide to ameliorate lung inflammation, these studies are the first to establish its efficacy in large animal models of disease.…”

Section: Introductionmentioning

confidence: 99%

Cell penetrating peptide inhibitors of Nuclear Factor-kappa B

Orange

May

2008

Cell. Mol. Life Sci.

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The nuclear factor kappa B (NF-κB) transcription factors are activated by a range of stimuli including pro-inflammatory cytokines. Active NF-κB regulates the expression of genes involved in inflammation and cell survival and aberrant NF-κB activity plays pathological roles in certain types of cancer and diseases characterized by chronic inflammation. NF-κB signaling is an attractive target for the development of novel anti-inflammatory or anti-cancer drugs and we discuss here how the method of peptide transduction has been used to specifically target NF-κB. Peptide transduction relies on the ability of certain small cell-penetrating peptides (CPPs) to enter cells, and a panel of CPP-linked inhibitors (CPP-Is) has been developed to directly inhibit NF-κB signaling. Remarkably, several of these NF-κB-targeting CPP-Is are effective in vivo and therefore offer exciting potential in the clinical setting.

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“…Myeloperoxidase, an enzyme present in leukocytes, is an index of tissue immune cell infiltration and was determined in ischemic and non-ischemic myocardial tissue samples as previously described [13].…”

Section: Methodsmentioning

confidence: 99%

Hypothermia and Postconditioning after Cardiopulmonary Resuscitation Reduce Cardiac Dysfunction by Modulating Inflammation, Apoptosis and Remodeling

et al. 2009

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BackgroundMild therapeutic hypothermia following cardiac arrest is neuroprotective, but its effect on myocardial dysfunction that is a critical issue following resuscitation is not clear. This study sought to examine whether hypothermia and the combination of hypothermia and pharmacological postconditioning are cardioprotective in a model of cardiopulmonary resuscitation following acute myocardial ischemia.Methodology/Principal FindingsThirty pigs (28–34 kg) were subjected to cardiac arrest following left anterior descending coronary artery ischemia. After 7 minutes of ventricular fibrillation and 2 minutes of basic life support, advanced cardiac life support was started according to the current AHA guidelines. After successful return of spontaneous circulation (n = 21), coronary perfusion was reestablished after 60 minutes of occlusion, and animals were randomized to either normothermia at 38°C, hypothermia at 33°C or hypothermia at 33°C combined with sevoflurane (each group n = 7) for 24 hours. The effects on cardiac damage especially on inflammation, apoptosis, and remodeling were studied using cellular and molecular approaches. Five animals were sham operated. Animals treated with hypothermia had lower troponin T levels (p<0.01), reduced infarct size (34±7 versus 57±12%; p<0.05) and improved left ventricular function compared to normothermia (p<0.05). Hypothermia was associated with a reduction in: (i) immune cell infiltration, (ii) apoptosis, (iii) IL-1β and IL-6 mRNA up-regulation, and (iv) IL-1β protein expression (p<0.05). Moreover, decreased matrix metalloproteinase-9 activity was detected in the ischemic myocardium after treatment with mild hypothermia. Sevoflurane conferred additional protective effects although statistic significance was not reached.Conclusions/SignificanceHypothermia reduced myocardial damage and dysfunction after cardiopulmonary resuscitation possible via a reduced rate of apoptosis and pro-inflammatory cytokine expression.

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Surfactant “fortification” by topical inhibition of nuclear factor-κB activity in a newborn piglet lavage model*

Cited by 20 publications

References 59 publications

The IκB kinase complex: master regulator of NF-κB signaling

The IκB kinase complex: master regulator of NF-κB signaling

Cell penetrating peptide inhibitors of Nuclear Factor-kappa B

Hypothermia and Postconditioning after Cardiopulmonary Resuscitation Reduce Cardiac Dysfunction by Modulating Inflammation, Apoptosis and Remodeling

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