Autotaxin production of lysophosphatidic acid mediates allergic asthmatic inflammation.
BACKGROUND
Bioactive lipid mediators, derived from membrane lipid precursors, are released into the airway and airspace where they bind high-affinity cognate receptors and may mediate asthma pathogenesis. Lysophosphatidic acid (LPA), a bioactive lipid mediator generated by the enzymatic activity of extracellular autotaxin (ATX), binds LPA receptors, resulting in an array of biological actions on cell proliferation, migration, survival, differentiation, and motility, and therefore could mediate asthma pathogenesis.


OBJECTIVE
To define a role for the ATX-LPA pathway in human asthma pathogenesis and a murine model of allergic lung inflammation.


METHODS
We investigated the profiles of LPA molecular species and the level of ATX exoenzyme in bronchoalveolar lavage fluids of human patients with asthma subjected to subsegmental bronchoprovocation with allergen. We interrogated the role of the ATX-LPA pathway in allergic lung inflammation using a murine allergic asthma model in ATX-LPA pathway-specific genetically modified mice.


RESULTS
Subsegmental bronchoprovocation with allergen in patients with mild asthma resulted in a remarkable increase in bronchoalveolar lavage fluid levels of LPA enriched in polyunsaturated 22:5 and 22:6 fatty acids in association with increased concentrations of ATX protein. Using a triple-allergen mouse asthma model, we showed that ATX-overexpressing transgenic mice had a more severe asthmatic phenotype, whereas blocking ATX activity and knockdown of the LPA2 receptor in mice produced a marked attenuation of Th2 cytokines and allergic lung inflammation.


CONCLUSIONS
The ATX-LPA pathway plays a critical role in the pathogenesis of asthma. These preclinical data indicate that targeting the ATX-LPA pathway could be an effective antiasthma treatment strategy.
1 Section of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine.
Gye Young
GY
Park
Yong Gyu
YG
Lee
Evgeny
E
Berdyshev
Sharmilee
S
Nyenhuis
Jian
J
Du
Panfeng
P
Fu
Irina A
IA
Gorshkova
Yongchao
Y
Li
Sangwoon
S
Chung
Manjula
M
Karpurapu
Jing
J
Deng
Ravi
R
Ranjan
Lei
L
Xiao
H Ari
HA
Jaffe
Susan J
SJ
Corbridge
Elizabeth A B
EA
Kelly
Nizar N
NN
Jarjour
Jerold
J
Chun
Glenn D
GD
Prestwich
Eleanna
E
Kaffe
Ioanna
I
Ninou
Vassilis
V
Aidinis
Andrew J
AJ
Morris
Susan S
SS
Smyth
Steven J
SJ
Ackerman
Viswanathan
V
Natarajan
John W
JW
Christman
D000485:Allergens / Q000494:pharmacology; D000818:Animals; D001249:Asthma / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology*; D008246:Lysophospholipids / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010727:Phosphoric Diester Hydrolases / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D000099189:Lysophospholipase D
D000485:Allergens; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid