title: Inhalation therapy with the synthetic TIP-like peptide AP318 attenuates pulmonary inflammation in a porcine sepsis model.
abstract: BACKGROUND
  The lectin-like domain of TNF-α can be mimicked by synthetic TIP peptides and represents an innovative pharmacologic option to treat edematous respiratory failure. TIP inhalation was shown to reduce pulmonary edema and improve gas exchange. In addition to its edema resolution effect, TIP peptides may exert some anti-inflammatory properties. The present study therefore investigates the influence of the inhaled TIP peptide AP318 on intrapulmonary inflammatory response in a porcine model of systemic sepsis.
  
  
  METHODS
  In a randomized-blinded setting lung injury was induced in 18 pigs by lipopolysaccharide-infusion and a second hit with a short period of ventilator-induced lung stress, followed by a six-hour observation period. The animals received either two inhalations with the peptide (AP318, 2×1 mg kg(-1)) or vehicle. Post-mortem pulmonary expression of inflammatory and mechanotransduction markers were determined by real-time polymerase chain reaction (IL-1β, IL-6, TNF-α, COX-2, iNOS, amphiregulin, and tenascin-c). Furthermore, regional histopathological lung injury, edema formation and systemic inflammation were quantified.
  
  
  RESULTS
  Despite similar systemic response to lipopolysaccharide infusion in both groups, pulmonary inflammation (IL-6, TNF-α, COX-2, tenascin-c) was significantly mitigated by AP318. Furthermore, a Western blot analysis shows a significantly lower of COX-2 protein level. The present sepsis model caused minor lung edema formation and moderate gas exchange impairment. Six hours after onset pathologic scoring showed no improvement, while gas exchange parameters and pulmonary edema formation were similar in the two groups.
  
  
  CONCLUSIONS
  In summary, AP318 significantly attenuated intrapulmonary inflammatory response even without the presence or resolution of severe pulmonary edema in a porcine model of systemic sepsis-associated lung injury. These findings suggest an anti-inflammatory mechanism of the lectin-like domain beyond mere edema reabsorption in endotoxemic lung injury in vivo.
authors: Department of Anesthesiology, Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany. hartmane@uni-mainz.de.
authors: Erik K
authors: EK
authors: Hartmann
authors: Department of Anesthesiology, Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany. alexander.ziebart@unimedizin-mainz.de.
authors: Alexander
authors: A
authors: Ziebart
authors: Department of Anesthesiology, Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany. rainerthomasmd@googlemail.com.
authors: Rainer
authors: R
authors: Thomas
authors: Department of Anesthesiology, Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany. smile_liuth2008@yahoo.cn.
authors: Tanghua
authors: T
authors: Liu
authors: Institute of Pathology, Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany. arno.schad@unimedizin-mainz.de.
authors: Arno
authors: A
authors: Schad
authors: Institute of Pathobiochemistry, Medical Center of the Johannes, Gutenberg-University, Duesbergweg 6, 55128, Mainz, Germany. tews@uni-mainz.de.
authors: Martha
authors: M
authors: Tews
authors: Institute of Pathobiochemistry, Medical Center of the Johannes, Gutenberg-University, Duesbergweg 6, 55128, Mainz, Germany. moosmann@uni-mainz.de.
authors: Bernd
authors: B
authors: Moosmann
authors: Department of Anesthesiology, Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany. kamuf@uni-mainz.de.
authors: Jens
authors: J
authors: Kamuf
authors: Department of Anesthesiology, Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany. bastian.duenges@unimedizin-mainz.de.
authors: Bastian
authors: B
authors: Duenges
authors: Department of Anesthesiology, Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany. thal@uni-mainz.de.
authors: Serge C
authors: SC
authors: Thal
authors: Department of Anesthesiology, Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, 55131, Mainz, Germany. david@uni-mainz.de.
authors: Matthias
authors: M
authors: David
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology*; D000280:Administration, Inhalation; D000818:Animals; D015153:Blotting, Western; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects* / Q000276:immunology; D010455:Peptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000276:immunology; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D018805:Sepsis / Q000276:immunology*; D013552:Swine; D019063:Tenascin / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D059467:Transcriptome / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D055397:Ventilator-Induced Lung Injury / Q000276:immunology*
chemical_list: C000609085:AP318 peptide; D015850:Interleukin-6; D008070:Lipopolysaccharides; D010455:Peptides; D010456:Peptides, Cyclic; D019063:Tenascin; D014409:Tumor Necrosis Factor-alpha; D051546:Cyclooxygenase 2