An association between neutrophils and immunoglobulin free light chains in the pathogenesis of chronic obstructive pulmonary disease.
BACKGROUND
Neutrophils are key players in chronic obstructive pulmonary disease (COPD), and increased numbers of neutrophils are present in sputum and lung tissue of patients with COPD. Interestingly, immunoglobulin free light chains (IgLC) are able to prolong the life of neutrophils; therefore, IgLC may contribute to the chronic state of inflammation.


OBJECTIVE
In this study, the relation between IgLC and COPD has been investigated.


METHODS
We investigated the presence of IgLC in different murine lung emphysema models. IgLC levels in serum from mice and patients with COPD were examined by Western blot analysis and ELISA, respectively. IgLC levels in lung tissue were determined by immunohistochemistry. Fluorescence-activated cell sorter and immunofluorescent analysis were used to detect binding between IgLC and human neutrophils. Interleukin-8 (CXCL8) release by neutrophils after IgLC incubation was measured by ELISA. The effect of F991, an IgLC antagonist, was examined on the neutrophil influx in murine lungs after 5 days of smoke exposure.


RESULTS
Increased levels of IgLC in serum of cigarette smoke-exposed and cigarette smoke extract-treated mice compared with control mice were observed. Patients with COPD showed increased serum IgLC and expression of IgLC in lung tissue compared with healthy volunteers. Interestingly, IgLC bound to neutrophils and activated neutrophils to release CXCL8. F991 inhibited the IgLC binding to neutrophils and reduced the smoke-induced neutrophil influx in murine lungs after smoke exposure.


CONCLUSIONS
This study describes for the first time an association between neutrophils and IgLC in the pathophysiology of COPD, which could open new avenues to targeted treatment of this chronic disease.
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, The Netherlands. s.braber@uu.nl
Saskia
S
Braber
Marco
M
Thio
Bart R
BR
Blokhuis
Paul A J
PA
Henricks
Pim J
PJ
Koelink
Tom
T
Groot Kormelink
Gillina F G
GF
Bezemer
Huib A M
HA
Kerstjens
Dirkje S
DS
Postma
Johan
J
Garssen
Aletta D
AD
Kraneveld
Frank A
FA
Redegeld
Gert
G
Folkerts
D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism*; D007958:Leukocyte Count; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D015999:Multivariate Analysis; D018375:Neutrophil Activation; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000503:physiopathology*; D011897:Random Allocation; D012494:Sampling Studies; D012906:Smoke / Q000009:adverse effects; D012907:Smoking / Q000009:adverse effects*
D015415:Biomarkers; D007147:Immunoglobulin Light Chains; D012906:Smoke