TABLE 1

Details of microarray studies published on lung homogenate (LH), laser capture microdissection (LCM), and isolated or circulating cells since 2001 with a focus on pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) associated with chronic lung diseases, displayed in chronological order

	Patient cohort	Mean age years	Mean mPAP mmHg	Biological material	Target molecule	Platform	Prominent genes	Prominent pathways/processes	First author [ref.]	GEO link
LH samples	6 controls (with the primary diagnosis of cervical carcinoma, adenocarcinoma of the lung, unknown primary diagnosis, head trauma, synovial cell carcinoma and lung carcinoma)	NA		LH, total RNA	mRNA	Affymetrix^#	TGFBR3, BMP2, MAPKK5, RACK1, APOC3, LAMR1/RPSA	Protein synthesis and degradation Endothelial cell biology Cell growth and apoptosis	Geraci [31]	NA
	6 PPH subjects (2 FPPH)	37	59	LH, total RNA	mRNA	Affymetrix^#			Geraci [31]	NA
	13 normal controls	60		LH, total RNA	mRNA	Agilent^¶	BMPR1A, BMPR2, PTGS2, VEGFA, ADAMTS9, CHL1, CYBB/NOX2, E2F1, ESR1, F2RL3, MYBL1, NCOA2, P2RY1, PF4, PLN, PPP2CA, TMOD3	Regulation of actin-based motility by Rho cAMP-mediated signalling Protein ubiquitination pathway	Rajkumar [32]	GSE15197
	18 PAH subjects	44	55
	8 IPF subjects with secondary PH	60	45
	9 normal controls (normal lung tissue specimens were obtained from organ donors whose lungs were not used for lung transplantation)	53		LH, total RNA	mRNA	Illumina⁺	CXCL10, FCN3, IGFBP7, SCGB1A1	Fibrosis IGF signalling caveolin-mediated endocytosis antigen presentation chemokine activity IL-17 signalling	Hsu [33]	GSE48149
	9 SSc-PF subjects	49	20
	9 SSc-PAH subjects	52	48
	10 IPF subjects	62	23
	8 IPAH subjects	35	60
	17 PH-IPF subjects	58	48	LH, total RNA	mRNA	Affymetrix	SPP1, MMP1, MMP7, MMP13, EDNRB, PTX3, S100A8	PH phenotype: cell proliferation, fibroblast migration noPH phenotype: proinflammatory genes	Mura [12]	GSE24988
	45 intermediate PH-IPF subjects	59	29
	22 IPF subjects	61	17
	7 IPAH subjects	43	53
	8 controls	47		LH, total RNA	mRNA	Affymetrix	CYP7B1	Bile acids metabolites	Zhao [34]	GSE53408
	8 PAH subjects	40	NA	LH, total RNA	mRNA	Affymetrix	CYP7B1	Bile acids metabolites	Zhao [34]	GSE53408
LCM	6 donors (nontransplanted donor lung tissue showing no evidence of vascular pathology)	47		PAs <500 µm, total RNA	mRNA	Agilent	DAAM1, RAC1, RHOA, ROCK, DSV, WNT11	Extracellular matrix and cytoskeleton Immune reaction WNT signaling pathway	Laumanns [35]	GSE10704
	6 IPAH subjects	28	102	PAs <500 µm, total RNA	mRNA	Agilent	DAAM1, RAC1, RHOA, ROCK, DSV, WNT11		Laumanns [35]	GSE10704
	7 donors (4 unused donor lung shavings and 3 normal lung sections obtained during resection of pulmonary carcinoid tumours)	45		PAs 100–450 µm, total RNA	mRNA	Affymetrix	STAT1, SMOC2, SFRP2	Amino acid metabolism AMP kinase signalling Ciliary neutrophic factor signalling Complement system Cellular growth/proliferation	Patel [36]	NA
	8 PH-IPF subjects	59	29
	8 non-PH-IPF subjects	63	12
	8 donors (downsized nontumorous nontransplanted donor lungs)	44		PAs <300µm, total RNA	mRNA	Agilent	COL3A1, TNC, COL6A3, THBS2, VWF	Retinol metabolism ECM receptor interaction	Hoffmann [6]	NA
	8 PH-IPF subjects	62	55
	8 PH-COPD subjects	57	53
Isolated cells	2 normal controls	NA		PASMCs treated with BMP-2, 200 nM for 24 h; passages 5–6	mRNA	Affymetrix	CAV2, MYCBP, FOS, ANXA5, CYC1, GATA2, TGFBR1, TGFBR2A, GADD34, HTR2B, F2R, ITPR1	Cell growth and contraction Apoptosis	Fantozzi [37]	GSE2559
	2 IPAH subjects	44	52	PASMCs treated with BMP-2, 200 nM for 24 h; passages 5–6	mRNA	Affymetrix		Cell growth and contraction Apoptosis	Fantozzi [37]	GSE2559
	3 normal controls	NA		HMVEC-L and HMVEC-C treated with 3, 24 or 48 h hypoxia; passages 6–7	mRNA	Affymetrix	GREM1, LIMCH1, SLM2, SPON1, ENPP2, PRKY, MPEG1, TM2D1, CXCR7, MYO1B, BDNF		Costello [38]	GSE11341
	9 normal controls	53		Fibroblasts, passage 3; total RNA	mRNA	Illumina	PODN, LOX, FHL2	Fibrosis IGF signalling Caveolin-mediated endocytosis Antigen presentation Chemokine activity Interleukin-17 signalling	Hsu [33]	GSE48149
	9 SSc-PF subjects	49	20
	9 SSc-PAH subjects	52	48
	10 IPF subjects	62	23
	6 IPAH subjects	35	60
	3 normal controls	NA		Primary HPASMCs treated with 24 and 48 h hypoxia; passages 6 and 8; miRNA	miRNA	Exiqon^§	miR-210		Gou [39]	NA
	3 controls (no history of pulmonary or cardiac disease or symptoms)	NA		HPASMCs up to passage 6, total RNA	mRNA	Affymetrix	BKB2R, PLK1, PLK4, ANLN, ANGPT1, DAPK1, SOD3	Cellular growth/proliferation/maintenance/movement Cell cycle/death/survival	Yu [40]	NA
	3 IPAH subjects	NA	NA
	3 HPAH subjects	NA	NA
Circulating cells	6 normal controls	39		PBMCs_, total RNA	mRNA	Affymetrix	ECGF1, ADM, HVEM	Inflammatory response Response to stress Cytochrome C oxidase Lysosome Intracellular signalling cascade	Bull [41].	GSE703
	7 IPAH subjects	43	60
	8 sPAH subjects	57	50
	5 healthy Caucasian controls	47		PBMCs, total RNA	mRNA	Affymetrix	DEFA1, DEFA3, S100P, PROK2	Inflammation Immune responses	Ulrich [42]	NA
	5 severe IPAH subjects	46	51	PBMCs, total RNA	mRNA	Affymetrix	DEFA1, DEFA3, S100P, PROK2	Inflammation Immune responses	Ulrich [42]	NA
	5 healthy controls	34		PBMCs, total RNA	mRNA	Affymetrix	MMP9, VEGF, EREG, IL8	Angiogenesis Chemotaxis Inflammation	Grigoryev [43]	NA
	9 IPAH subjects	49	50
	10 PAH-SSc	61	51
	3 unaffected BMPR2 mutation carriers	73	NA	Cultured lymphocytes, total RNA	mRNA	Affymetrix	CYP1B1	Stress response Actin organisation Proliferation Ras-related G-proteins Calcium balance	West [44]	GSE10767
	4 affected BMPR2 mutation carriers	22	NA	Cultured lymphocytes, total RNA	mRNA	Affymetrix	CYP1B1		West [44]	GSE10767
	10 healthy controls	NA		PBMCs, total RNA	mRNA	Agilent	ICAM1, IFNGR1, IL1B, IL13RA1, JAK2, AIF1, CCR1, ALAS2, TIMP2	Vascular injury Proliferation Inflammatory responses	Pendergrass [45]	GSE19617
	21 lSSc subjects without PAH	55	19
	15 lSSc-PAH subjects	70	47
	10 SSc	51	NA	PBMCs, total RNA	mRNA	Affymetrix	IL7R	Inflammation Immunity	Risbano [46]	GSE22356
	10 SSc-PAH	62	80	PBMCs, total RNA	mRNA	Affymetrix	IL7R	Inflammation Immunity	Risbano [46]	GSE22356
	41 healthy controls	45		PBMCs, total RNA	mRNA	Illumina	ALAS2, ERAF/AHSP	Erythrocyte maturation	Cheadle [47]	GSE33463
	30 IPAH subjects	52	NA
	19 SSc subjects	55	NA
	42 SSc-PAH subjects	60	NA
	8 SSc-PH-ILD subjects	61	NA
	8 healthy controls	40		Plasma, miRNA	miRNA	Geniom^ƒ	miR-150		Rhodes [11]	NA
	8 treatment-naive PAH subjects	40	57	Plasma, miRNA	miRNA	Geniom^ƒ	miR-150		Rhodes [11]	NA
	8 healthy controls	NA	17	Plasma, miRNA	miRNA	NA	miR-451, miR-1246, miR-23b, miR-130a, miR-191		Wei [17]	NA
	15 moderate PH subjects	NA	29
	17 severe PH	NA	46
	28 controls	43		PBMCs, total RNA	mRNA	Agilent	TCF7, IL7R	Metabolic process T-cell receptor signalling pathway	Chesné [48]	GSE38267
	13 PAH subjects	41	67
	23 CF subjects	24	NA
	22 healthy controls (free from known cardiovascular disease)	NA		Blood-derived lymphocyte culture, 6 weeks); total RNA	mRNA	Affymetrix	DSG2, RHOQ	Cytoskeletal/Rho GTPase genes Cell adhesion genes Transcription factors Developmental pathways	Hemnes [13]	NA (series pending)
	32 idiopathic and heritable VN-PAH subjects	37	60
	8 idiopathic and heritable VR-PAH subjects	27	46
	10 controls	NA		Plasma, miRNA	miRNA	Affymetrix	miR-23a		Sarrion [49]	NA
	12 IPAH subjects	56	49	Plasma, miRNA	miRNA	Affymetrix	miR-23a		Sarrion [49]	NA

GEO: Gene Omnibus; NA: not available; PPH: primary pulmonary hypertension; FPPH: familial primary pulmonary hypertension; mPAP: mean pulmonary artery pressure; IFP: idiopathic pulmonary fibrosis; SSc: systemic sclerosis; PF: pulmonary fibrosis; IPAH: idiopathic pulmonary arterial hypertension; COPD: chronic obstructive pulmonary disease; HPAH: heritable pulmonary arterial hypertension; sPAH: secondary pulmonary arterial hypertension; BMPR2: bone morphogenetic protein receptor II; lSSc: limited systemic sclerosis; ILD: interstitial lung disease; CF: cystic fibrosis; VN: vasodilator-nonresponsive; VR: vasodilator responsive; PA: pulmonary artery; PASMC: pulmonary artery smooth muscle cell; BMP: bone morphogenetic protein; HMVEC-L: human lung microvascular endothelial cell; HMVEC-C: human cardiac microvascular endothelial cell; HPASMC: human pulmonary smooth muscle cell; PMBC: peripheral blood mononuclear cell; miRNA: microRNA; TGFBR3: transforming growth factor-β receptor III; BMP2: bone morphogenetic protein 2; MAPKK5: mitogen-activated protein kinase kinase 5; RACK1: receptor for activated C kinase 1; APOC3: apolipoprotein C-III; LAMR1: laminin receptor 1; RPSA: ribosomal protein SA; BMPR1A: bone morphogenetic protein receptor IA; PTGS2: prostaglandin–endoperoxide synthase 2; VEGFA: vascular endothelial growth factor A; ADAMTS9: a disintegrin-like and metalloprotease with thrombospondin type 1 motif 9; CHL1: cell adhesion molecule L1-like; E2F1: E2F transcription factor 1; CYBB: cytochrome b-245 heavy chain; NOX2: NADPH oxidase 2; ESR1: oestrogen receptor 1; F2RL3: coagulation factor II receptor-like 3; MYBL1: v-Myb avian myeloblastosis viral oncogene homologue-like 1; NCOA2: nuclear receptor coactivator 2; P2RY1: purinergic receptor P2Y, G-protein coupled, 1; PF4: platelet factor 4; PLN: phospholamban; PPP2CA: protein phosphatase 2, catalytic subunit, α-isozyme; TMOD3: tropomodulin 3; CXCL10: interferon-γ-inducible protein 10; FCN3: ficolin 3; IGFBP7: insulin-like growth factor-binding protein 7; SCGB1A1: secretoglobin 1A1; SPP1: secreted phosphoprotein 1 (osteopontin); MMP1: matrix metalloprotease 1; MMP7: matrix metalloprotease 7; MMP13: matrix metalloprotease 13; EDNRB: endothelin receptor B; PTX3: pentraxin 3; CYP7B1: cytochrome P450 7B1; DAAM1: Dishevelled-associated activator of morphogenesis 1; RAC1: Ras-related C3 botulinum toxin substrate 1; RHOA: Ras homologue A; ROCK: RHO kinase; DSV: Dishevelled; WTN11: Wingless member 11; STAT1: signal transducer and activator of transcription 1; SMOC2: SPARC-related modular calcium binding 2; SFRP2: secreted Frizzled-related protein 2; COL3A1: collagen IIIA1; TNC: tenascin C; COL6A3: collagen VIA3; THBS2: thrombospondin 2;VWF: von Willebrand factor; CAV2: caveolin 2; MYCBP: Myc binding protein; FOS: FBJ murine osteosarcoma viral oncogene homologue; ANXA5: annexin A5; CYC1: cytochrome C1; GATA2: GATA binding protein 2; TGFBR1: transforming growth factor-β receptor I; TGFBR2A: transforming growth factor-β receptor IIα; GADD34: growth arrest- and DNA damage-inducible protein 34; HTR2B: 5-hydroxytryptamine receptor 2B; F2R: coagulation factor II receptor; ITPR1: inositol trisphosphate receptor 1; GREM1: Gremlin; LIMCH1: LIM and calponin homology domains 1; SLM2: Sam68-like mammalian protein 2; SPON1: spondin 1; ENPP2: ectonucleotide pyrophosphatase/phosphodiesterase 2; PRKY: protein kinase, Y-linked, pseudogene; MPEG1: macrophage expressed 1; TM2D1: TM2 domain-containing 1; MYO1B: myosin IB; BDNF: brain-derived neurotrophic factor; PODN: podocan; LOX: lysyl oxidase; FHL2: four and a half LIM domains 2; BKB2R: bradykinin receptor B2; PLK1: Polo-like kinase 1; PLK4: Polo-like kinase 4; ANLN: anillin; ANGPT1: angiopoietin 1; DAPK1: death-associated protein kinase 1; SOD3: superoxide dismutase 3; ECGF1: endothelial growth factor 1; ADM: adrenomedullin; HVEM: herpesvirus entry mediator; DEFA1: defensin α1; DEFA3: defensin α3; S100P: S100 calcium binding protein 3; PROK2: prokineticin 2; MMP9: matrix metalloprotease 9; VEGF: vascular endothelial growth factor; EREG: epiregulin; IL8: interleukin-8; CYP1B1: cytochrome P450 1B1; ICAM1: intercellular adhesion molecule 1; IFNGR1: interferon-γ receptor I; IL1B: interleukin-1β; IL13RA1: interleukin-13 receptor α1; JAK2: Janus kinase 2; AIF1: allograft inflammatory factor 1; ALAS2: 5′-aminolevulinate synthase 2; TIMP2: tissue inhibitor of metalloprotease 2; IL7R: interleukin-7 receptor; ERAF: erythroid differentiation associated factor; AHSP: α-haemoglobin stabilising factor; TCF7: T-cell factor 7; DSG2: desmoglein 2; RHOQ: Ras homologue family member Q; IGF: insulin-like growth factor; GTP: guanosine triphosphate; ECM: extracellular matrix. ^#: Affymetrix Inc., Santa Clara, CA, USA; ^¶: Agilent Technologies, Santa Clara, CA, USA; ⁺: Illumina Inc., San Diego, CA, USA; ^§: Exiqon A/S, Vedbæk, Denmark; ^ƒ: Geniom Biochip MPEA Homo sapiens (Febit Biomed GmbH, Heidelberg, Germany).