Prosurvival activity for airway neutrophils in severe asthma.
BACKGROUND
Airway neutrophilia is a recognised feature of chronic severe asthma, but the mechanisms that underlie this phenomenon are unknown. Evidence for factors present in airway secretions that prolong neutrophil survival has been sought and it has been hypothesised that these might be augmented in neutrophilic asthma.


METHODS
Non-smoking subjects with severe asthma (SA) or mild asthma (MA) and healthy control subjects (HC) underwent sputum induction. The SA group was subdivided into subjects with neutrophil counts above (SA-high) and those within the normal range (SA-low). Apoptotic neutrophils were enumerated in the cellular phase while the fluid phase was assessed for its ability to prolong the in vitro survival of blood-derived neutrophils using morphometric and flow cytometric analyses.


RESULTS
There was a significant difference between all four subject groups with respect to the percentage of apoptotic sputum neutrophils (Kruskal-Wallis, p=0.042). Cuzick test showed a highly significant (p=0.008) trend towards decreasing numbers of apoptotic neutrophils across the four groups with increasing asthma severity and neutrophil count. The sputum antiapoptotic activity was also different between the groups (p=0.039), with a highly significant (p=0.005) decreasing trend across the four groups. The survival effect could not be inhibited by blocking selective chemotaxin receptors, neutralising neutrophil survival factors, inhibiting phosphatidylinositol-3-kinase (using LY294002) or with pertussis toxin pretreatment. Similarly, it could not be explained by lipopolysaccharide contamination or by the presence of inhaled corticosteroids in sputum.


CONCLUSIONS
These data demonstrate the capacity of as yet unidentified factor(s) in the airways of subjects with asthma to delay human neutrophil apoptosis and extend their lifespan as a potential mechanism contributing to unresolving airways neutrophilia in severe asthma.
Uddin
Mohib
M
Southampton NIHR Respiratory Biomedical Research Unit, Division of Infection, Inflammation and Immunity, University of Southampton School of Medicine, Sir Henry Wellcome Laboratories, South Block, Southampton General Hospital, Southampton, UK.
Nong
Guangmin
G
Ward
Jonathan
J
Seumois
Grégory
G
Prince
Lynne R
LR
Wilson
Susan J
SJ
Cornelius
Victoria
V
Dent
Gordon
G
Djukanovic
Ratko
R
D000328:Adult; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001249:Asthma / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008168:Lung / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D015735:Mifepristone / Q000494:pharmacology; D020556:Neutrophil Infiltration / Q000502:physiology; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000502:physiology; D013183:Sputum / Q000166:cytology
D016207:Cytokines; D011965:Receptors, Glucocorticoid; D015735:Mifepristone