PMID- 30500834
OWN - NLM
STAT- MEDLINE
DCOM- 20190422
LR  - 20200309
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 13
IP  - 11
DP  - 2018
TI  - Human lung tissue provides highly relevant data about efficacy of new 
      anti-asthmatic drugs.
PG  - e0207767
LID - 10.1371/journal.pone.0207767 [doi]
LID - e0207767
AB  - Subgroups of patients with severe asthma are insensitive to inhaled 
      corticosteroids and require novel therapies on top of standard medical care. 
      IL-13 is considered one of the key cytokines in the asthma pathogenesis, however, 
      the effect of IL-13 was mostly studied in rodents. This study aimed to assess 
      IL-13 effect in human lung tissue for the development of targeted therapy 
      approaches such as inhibition of soluble IL-13 or its receptor IL-4Ralpha subunit. 
      Precision-cut lung slices (PCLS) were prepared from lungs of rodents, non-human 
      primates (NHP) and humans. Direct effect of IL-13 on human lung tissue was 
      observed on inflammation, induction of mucin5AC, and airway constriction induced 
      by methacholine and visualized by videomicroscopy. Anti-inflammatory treatment 
      was evaluated by co-incubation of IL-13 with increasing concentrations of 
      IL-13/IL-13 receptor inhibitors. IL-13 induced a two-fold increase in mucin5AC 
      secretion in human bronchial tissue. Additionally, IL-13 induced release of 
      proinflammatory cytokines eotaxin-3 and TARC in human PCLS. Anti-inflammatory 
      treatment with four different inhibitors acting either on the IL-13 ligand itself 
      (anti-IL-13 antibody, similar to Lebrikizumab) or the IL-4Ralpha chain of the 
      IL-13/IL-4 receptor complex (anti-IL-4Ralpha #1, similar to AMG 317, and #2, similar 
      to REGN668) and #3 PRS-060 (a novel anticalin directed against this receptor) 
      could significantly attenuate IL-13 induced inflammation. Contrary to this, IL-13 
      did not induce airway hyperresponsiveness (AHR) in human and NHP PCLS, although 
      it was effective in rodent PCLS. Overall, this study demonstrates that IL-13 
      stimulation induces production of mucus and biomarkers of allergic inflammation 
      in human lung tissue ex-vivo but no airway hyperresponsiveness. The results of 
      this study show a more distinct efficacy than known from animals models and a 
      clear discrepancy in AHR induction. Moreover, it allows a translational approach 
      in inhibitor profiling in human lung tissue.
FAU - Danov, Olga
AU  - Danov O
AUID- ORCID: 0000-0001-6860-5610
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical 
      Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of 
      the German Center for Lung Research (DZL), Hannover, Germany.
FAU - Jimenez Delgado, Sharon Melissa
AU  - Jimenez Delgado SM
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical 
      Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of 
      the German Center for Lung Research (DZL), Hannover, Germany.
FAU - Obernolte, Helena
AU  - Obernolte H
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical 
      Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of 
      the German Center for Lung Research (DZL), Hannover, Germany.
FAU - Seehase, Sophie
AU  - Seehase S
AD  - Research Center Borstel, Airway Research Center North (ARCN), Member of the 
      German Center for Lung Research (DZL), Borstel, Germany.
FAU - Dehmel, Susann
AU  - Dehmel S
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical 
      Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of 
      the German Center for Lung Research (DZL), Hannover, Germany.
FAU - Braubach, Peter
AU  - Braubach P
AD  - Institute for Pathology, Hannover Medical School, Biomedical Research in Endstage 
      and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for 
      Lung Research (DZL), Hannover, Germany.
FAU - Fieguth, Hans-Gerd
AU  - Fieguth HG
AD  - KRH Klinikum Siloah-Oststadt-Heidehaus, Hannover, Germany.
FAU - Matschiner, Gabriele
AU  - Matschiner G
AD  - Pieris AG, Freising-Weihenstephan, Germany.
FAU - Fitzgerald, Mary
AU  - Fitzgerald M
AD  - Pieris AG, Freising-Weihenstephan, Germany.
FAU - Jonigk, Danny
AU  - Jonigk D
AD  - Institute for Pathology, Hannover Medical School, Biomedical Research in Endstage 
      and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for 
      Lung Research (DZL), Hannover, Germany.
FAU - Knauf, Sascha
AU  - Knauf S
AUID- ORCID: 0000-0001-5744-4946
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical 
      Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of 
      the German Center for Lung Research (DZL), Hannover, Germany.
AD  - Pathology Unit, German Primate Center, Leibniz-Institute, Gottingen, Germany.
FAU - Pfennig, Olaf
AU  - Pfennig O
AD  - KRH Klinikum Siloah-Oststadt-Heidehaus, Hannover, Germany.
FAU - Warnecke, Gregor
AU  - Warnecke G
AD  - Division of Cardiac, Thoracic, Transplantation, and Vascular Surgery, Hannover 
      Medical School, Biomedical Research in Endstage and Obstructive Lung Disease 
      Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, 
      Germany.
FAU - Wichmann, Judy
AU  - Wichmann J
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical 
      Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of 
      the German Center for Lung Research (DZL), Hannover, Germany.
AD  - Pathology Unit, German Primate Center, Leibniz-Institute, Gottingen, Germany.
FAU - Braun, Armin
AU  - Braun A
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical 
      Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of 
      the German Center for Lung Research (DZL), Hannover, Germany.
AD  - Institute of Immunology, Hannover Medical School, Hannover, Germany.
FAU - Sewald, Katherina
AU  - Sewald K
AD  - Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Biomedical 
      Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of 
      the German Center for Lung Research (DZL), Hannover, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181130
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Anti-Asthmatic Agents)
RN  - 0 (Chemokine CCL17)
RN  - 0 (Chemokine CCL26)
RN  - 0 (Interleukin-13)
RN  - 0 (Mucins)
RN  - 0 (Receptors, Interleukin-13)
SB  - IM
MH  - Anti-Asthmatic Agents/*pharmacology
MH  - Bronchi/drug effects/metabolism
MH  - Chemokine CCL17/metabolism
MH  - Chemokine CCL26/metabolism
MH  - Humans
MH  - Interleukin-13/*pharmacology
MH  - Lung/*drug effects/metabolism/pathology
MH  - Mucins/biosynthesis
MH  - Receptors, Interleukin-13/metabolism
PMC - PMC6267969
COIS- Pieris provided support in the form of salaries for authors GM and MF. This does 
      not alter our adherence to PLOS ONE policies on data sharing and materials. There 
      are no patents, products in development or marketed products to declare.
EDAT- 2018/12/01 06:00
MHDA- 2019/04/23 06:00
PMCR- 2018/11/30
CRDT- 2018/12/01 06:00
PHST- 2018/03/25 00:00 [received]
PHST- 2018/11/06 00:00 [accepted]
PHST- 2018/12/01 06:00 [entrez]
PHST- 2018/12/01 06:00 [pubmed]
PHST- 2019/04/23 06:00 [medline]
PHST- 2018/11/30 00:00 [pmc-release]
AID - PONE-D-18-09050 [pii]
AID - 10.1371/journal.pone.0207767 [doi]
PST - epublish
SO  - PLoS One. 2018 Nov 30;13(11):e0207767. doi: 10.1371/journal.pone.0207767. 
      eCollection 2018.