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Resolution of leucocyte-mediated mucosal diseases. A novel in vivo paradigm for drug development

Persson, Carl LU and Uller, Lena LU (2012) In British Journal of Pharmacology 165(7). p.2100-2109
Abstract
Removal of disease-driving inflammatory leucocytes is central to resolution of inflammation. The current pharmacological dogma teaches leucocyte elimination through apoptosis followed by phagocytosis. However, actual resolving roles of apoptotic-phagocytic processes have been difficult to demonstrate in the major diseases that are characterized by mucosal tissue inflammation. Many current in vivo observations rather demonstrate that leucocyte elimination occurs by transepithelial locomotion. Findings in diseased gut and bladder mucosae support this notion. Respiratory disease data are particularly compelling. Eosinophils and neutrophils abound in sputum and tracheal aspirates during treatment-induced recovery from severe asthma. Prolonged... (More)
Removal of disease-driving inflammatory leucocytes is central to resolution of inflammation. The current pharmacological dogma teaches leucocyte elimination through apoptosis followed by phagocytosis. However, actual resolving roles of apoptotic-phagocytic processes have been difficult to demonstrate in the major diseases that are characterized by mucosal tissue inflammation. Many current in vivo observations rather demonstrate that leucocyte elimination occurs by transepithelial locomotion. Findings in diseased gut and bladder mucosae support this notion. Respiratory disease data are particularly compelling. Eosinophils and neutrophils abound in sputum and tracheal aspirates during treatment-induced recovery from severe asthma. Prolonged sputum neutrophilia, along with clinical improvement, follows upon smoking cessation in COPD. Eosinophils, neutrophils, lymphocytes, mast cells, and dendritic cells also move in large numbers into the bronchial lumen at spontaneous inflammation resolution following allergen challenge in allergic rhinitis and asthma. A corresponding reduction of infiltrated cells in the bronchial mucosal tissue demonstrates efficiency of the transepithelial elimination pathway. Underscoring its operational role, drugs impeding transepithelial elimination of leucocytes aggravate mucosal/parenchymal inflammation. Hence, relying on lumen cell data alone can lead to paradoxical conclusions regarding anti-inflammatory drug efficacy. Conversely, drugs promoting non-injurious transepithelial elimination of leucocytes could resolve mucosal inflammatory diseases. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
inflammation resolution, transepithelial migration, IBD, COPD, asthma, drug toxicity, drug opportunity
in
British Journal of Pharmacology
volume
165
issue
7
pages
2100 - 2109
publisher
The British Pharmacological Society
external identifiers
  • wos:000301281700009
  • pmid:22053825
  • scopus:84858230745
ISSN
1476-5381
DOI
10.1111/j.1476-5381.2011.01772.x
language
English
LU publication?
yes
id
d0ff6cd7-1e60-4f97-9f54-3b536f1160ac (old id 2221138)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22053825?dopt=Abstract
date added to LUP
2011-12-02 19:18:24
date last changed
2017-01-01 06:12:46
@article{d0ff6cd7-1e60-4f97-9f54-3b536f1160ac,
  abstract     = {Removal of disease-driving inflammatory leucocytes is central to resolution of inflammation. The current pharmacological dogma teaches leucocyte elimination through apoptosis followed by phagocytosis. However, actual resolving roles of apoptotic-phagocytic processes have been difficult to demonstrate in the major diseases that are characterized by mucosal tissue inflammation. Many current in vivo observations rather demonstrate that leucocyte elimination occurs by transepithelial locomotion. Findings in diseased gut and bladder mucosae support this notion. Respiratory disease data are particularly compelling. Eosinophils and neutrophils abound in sputum and tracheal aspirates during treatment-induced recovery from severe asthma. Prolonged sputum neutrophilia, along with clinical improvement, follows upon smoking cessation in COPD. Eosinophils, neutrophils, lymphocytes, mast cells, and dendritic cells also move in large numbers into the bronchial lumen at spontaneous inflammation resolution following allergen challenge in allergic rhinitis and asthma. A corresponding reduction of infiltrated cells in the bronchial mucosal tissue demonstrates efficiency of the transepithelial elimination pathway. Underscoring its operational role, drugs impeding transepithelial elimination of leucocytes aggravate mucosal/parenchymal inflammation. Hence, relying on lumen cell data alone can lead to paradoxical conclusions regarding anti-inflammatory drug efficacy. Conversely, drugs promoting non-injurious transepithelial elimination of leucocytes could resolve mucosal inflammatory diseases.},
  author       = {Persson, Carl and Uller, Lena},
  issn         = {1476-5381},
  keyword      = {inflammation resolution,transepithelial migration,IBD,COPD,asthma,drug toxicity,drug opportunity},
  language     = {eng},
  number       = {7},
  pages        = {2100--2109},
  publisher    = {The British Pharmacological Society},
  series       = {British Journal of Pharmacology},
  title        = {Resolution of leucocyte-mediated mucosal diseases. A novel in vivo paradigm for drug development},
  url          = {http://dx.doi.org/10.1111/j.1476-5381.2011.01772.x},
  volume       = {165},
  year         = {2012},
}