Autotaxin and lysophosphatidic acid signalling in lung pathophysiology

Table 1 Expression of lysophosphatidic acid receptor in pulmonary cell types and leukocytes

Cell type	LPAR1	LPAR2	LPAR3	LPAR4	LPAR5	LPAR6	Ref.
NHBEs	+++	++	+++	-	+	+	[41]
NHBEs	+++	++	+++	-	++	+	[59]
NHBEs	++	++	++	-	NA	NA	[43]
HBE	++	++	NA	NA	NA	NA	[56]
HBE (BEAS-2B)	++	++	++	+	++	+	[59]
HBE (HBEpCs)	+++	+	++	+	+	NA	[209]
HBE (HBEpCs)	++	++	++	NA	NA	NA	[46]
HBE (HBEpCs)	++	++	++	NA	NA	NA	[49]
HBE (HBEpCs)	++	++	++	NA	NA	NA	[68]
Primary mouse tracheal EpCs	++	+++	++	++	-	NA	[57]
NHBE cells	++	++	++	-	NA	NA	[43]
A549 alveolar epithelial carcinoma	++	NA	NA	NA	NA	NA	[40]
A549 alveolar epithelial carcinoma	+++	+	-	-	NA	NA	[74]
NCI-H522 lung epithelial carcinoma	-	++	+	-	NA	NA	[74]
RLCNR rat lung adenocarcinoma	NA	NA	-	NA	++	NA	[283]
Primary mouse lung fibroblasts	+++	+	+	+	++	NA	[31]
human fetal lung fibroblasts MRC5	+++	++	++	+	+	NA	[226]
Mouse embryonic fibroblasts	+++	++	+	+++	+	NA	[101]
NHLFs CCL-151	+++	+	++	+	+	++	[81]
NHLFs	++	++	NA	NA	NA	NA	[42]
Primary mouse lung endothelial	++	+	-	+++	+	NA	[31]
HPAECs	+	++	+	+	+	+++	[106]
HMVECs	+	++	+	+	+	+++	[106]
HEV ECs	NA	NA	NA	++	NA	++	[116]
Human eosinophils	+	-	+	NA	NA	NA	[148]
Primary mouse neutrophils	-	+++	-	-	+	NA	[31]
Primary mouse alveolar macrophages	-	+	+	+	+	NA	[31]
Human alveolar macrophages	+	++	++	NA	NA	NA	[158]
Rat alveolar macrophages	++	+	-	NA	NA	NA	[158]
Human monocytes	+	-	-	NA	NA	NA	[176]
Mouse DCs	++	++	++	NA	NA	NA	[58]
Human immature DCs	+	+	+	NA	NA	NA	[172]
Human mature DCs	+	+	+	NA	NA	NA	[172]
Human immature DCs	-	+	-	NA	NA	NA	[174]
Human mature DCs	-	+	-	NA	NA	NA	[174]
Mouse immature DCs	++	+	+++	++	+++	NA	[175]
Mouse mature DCs	+++	+	+	++	++	NA	[175]
Jurkat T cells	+	+++	-	NA	NA	NA	[178]
Jurkat T cells	+	+	+	NA	NA	NA	[295]
Human CD4 T cells	+	+++	NA	NA	NA	NA	[177]
Human CD4 T cells	+	+++	-	NA	NA	NA	[176]
Human CD8 T cells	-	-	-	NA	NA	NA	[176]
Mouse CD4 T cells	+	+	+	+	+	NA	[31]
Mouse CD8 T cells	+	+++	+	+	++	NA	[31]
Human B lymphocytes	-	+	+	NA	NA	NA	[176]
Human platelets	+	NA	+	NA	NA	NA	[296]
Human platelets	+	+	+	NA	NA	NA	[295]
Human platelets	+	+	+	+	+	NA	[297]
Human mast cells	+	+	+	+	NA	NA	[199]
Human mast cells	+	+	+	-	NA	NA	[200]
Human mast cells	-	++	+	-	+++	++	[201]
Lung resident mesenchymal stem cells	+++	+	+	NA	NA	NA	[298]

+++: Strong expression; ++: Moderate expression; +: Low expression; -: No expression; NA: Not available; LPAR: Lysophosphatidic acid receptor; NHBEs: Normal human bronchial epithelial; HBE: Human bronchial epithelial; HBEpCs: Human bronchial epithelial cells; NHLFs: Normal human lung fibroblasts; ECs: Endothelial cells; HPAECs: Human pulmonary arterial ECs; HMVECs: Human pulmonary microvascular ECs; HMVECs: Human pulmonary microvascular ECs; HEVs: High endothelial venules; DCs: Dendritic cells.

Table 2 Lysophosphatidic acid effects on different cell types

Cell type	Primary	Species	LPA effect	Receptor	Experiment	Carrier	Ref
Alveolar and bronchial epithelial	Yes	Mouse	Apoptosis	LPAR1	In vivo	Biological fluid	[41]
Alveolar and bronchial epithelial	Yes	Mouse	Apoptosis	LPAR2	In vivo	Biological fluid	[41,42]
NHBEs	Yes	Human	(anchorage dependent) Apoptosis	LPAR1	In vitro	FAF BSA	[41]
NHBEs	Yes	Human	TSLP, CCL20 induction		In vitro	No	[50]
NHBEs	Yes	Human	TGF-β activation	LPAR2	In vitro	No	[43]
NHBEs	Yes	Human	Induction of Soluble ST2 expression	LPAR1,3	In vitro	NA	[61]
Bronchial epithelial (HBEpCs)	Yes	Human	EGFR transactivation, IL-8 secretion		In vitro	BSA; BSA	[46,49]
Bronchial epithelial (HBEpCs)	Yes	Human	Induction of IL-13 Ralpha 2	Gαi linked	In vitro	No	[54]
Bronchial epithelial (HBEpCs)	Yes	Human	Epithelial barrier integrity enhancement	LPAR1,3	In vitro	NA; BSA	[56,209]
Bronchial epithelial (HBEpCs)	Yes	Human	Decrease of EGFR-EGF binding		In vitro	BSA	[66]
Bronchial epithelial (HBEpCs)	Yes	Human	COX-2 expression, PGE2 secretion	Gαi linked	In vitro	No	[63]
Bronchial epithelial (HBEpCs)	Yes	Human	PDGFR-β transactivation		In vitro	BSA	[68]
Bronchial epithelial (HBEpCs)	Yes	Human	c-Met redistribution on the membrane		In vitro	No	[70,299]
Bronchial epithelial (BEAS-2B)	No	Human	EGFR transactivation		In vitro	BSA	[66]
Bronchial epithelial (BEAS-2B)	No	Human	RANTES inhibition	LPAR1	In vitro	FAF BSA	[59]
R3/1 Alveolar epithelial	No	Rat	Inhibition of attachment		In vitro	FAF BSA	[41]
Tracheal epithelial	Yes	Mouse	COX-2 expression, PGE2 secretion	LPAR2	In vitro/vivo	No	[57]
H292 lung cancer epithelial	No	Human	Decrease of EGFR-EGF binding		In vitro	BSA	[66]
A549 alveolar epithelial carcinoma	No	Human	Decrease of EGFR-EGF binding		In vitro	BSA	[66]
A549 alveolar epithelial carcinoma	No	Human	p53 decrease		In vitro	FAF BSA	[73]
A549 alveolar epithelial carcinoma	No	Human	Cell migration	LPAR1	In vitro	BSA; BSA	[40,74]
NCI-H522 lung epithelial carcinoma	No	Human	Cell motility		In vitro	BSA	[74]
Fetal lung fibroblasts (HFL1)	No	Human	Chemotaxis		In vitro	Biological fluid	[31]
NLFs CCL151	No	Human	Proliferation, EGFR ectodomain shedding	Gi/o linked	In vitro	No	[81]
Fetal lung fibroblasts MRC5	No	Human	proliferation	LPAR1,3	In vitro	No	[226]
Fetal lung fibroblasts IMR-90	No	Human	Chemotaxis	LPAR1	In vitro		[95]
NLFs	Yes	Human	Differentiation, TGF-β expression and signaling	LPAR2	In vitro	No	[42]
Lung fibroblasts	Yes	Mouse	Differentiation, TGF-β expression and signaling	LPAR2	In vitro	No	[42]
Lung fibroblasts	Yes	Mouse	Chemotaxis	LPAR1	In vitro	FAF BSA	[31]
Lung fibroblasts	Yes	Mouse	Protection from apoptosis	LPAR1	In vitro	FAF BSA	[41]
NIH 3T3 fibroblasts	No	Mouse	Protection from apoptosis, proliferation	Gi linked	In vitro	FAF BSA	[99]
NIH 3T3 fibroblasts	No	Mouse	Migration, protection from apoptosis, proliferation		In vitro	BSA	[100]
Rat1/c-Myc fibroblasts	No	Rat	Protection from apoptosis		In vitro	FAF BSA	[99]
Lung endothelial	Yes	Mouse	Vascular leak/extravasation	LPAR1	In vivo	Biological fluid	[31]
HPAECs pulmonary endothelial	Yes	Human	Increase of the endothelial layer permeability	LPAR6	In vitro	FAF BSA	[106]
BPAE pulmonary artery endothelial	No	Bovine	Migration, chemotaxis		In vitro	FAF BSA	[127-129]
Smooth muscle cells	Yes	Rabbit, cat	Contraction		Ex vivo	BSA	[140]
HASM airway smooth muscle cells	Yes	Human	Proliferation, stimulation of EGFR signaling		In vitro	NA; BSA	[139,141]
HASM airway smooth muscle cells	Yes	Human	Activation of TGF-β		In vitro	NA	[143]
Dendritic cells	Yes	Mouse	Inhibition of activation	LPAR2	In vitro, in vivo	FAF BSA	[58]
Lung resident mesenchymal stem cells	Yes	Human	Migration	LPAR1	In vitro	No	[298]

LPA: Lysophosphatidic acid; NHBEs: Normal bronchial epithelial; HBEpCs: Human bronchial epithelial cells; BEAS-2B: Bronchial epithelial cell line; NLFs: Normal lung fibroblasts; HPAECs: Human pulmonary arterial endothelial cells; LPAR: Lysophosphatidic acid receptor; NA: Not available; TSLP: Thymic stromal lymphopoietin; TGF-β: Transforming growth factor beta; EGFR: Epidermal growth factor receptor; BSA: Bovine serum albumin; FAF: Fatty acid free.