Table 2.

PI3K, and its individual isoforms, as targets in respiratory disease research

Target	Disease	Model	Research tool	Targeting impact	Refs
PI3K	ALI-ARDS	Endotoxin-induced (in vitro)	Inhibitor	Reduced expression of IL-1β and TNF-α in cultured neutrophils	46
		Endotoxin-Induced (in vivo)	Inhibitor	No reduction in IL-6 or CXCL2 levels	54
		Endotoxin-Induced (in vivo)	Inhibitor	Decreased oedema, neutrophil infiltration and inflammatory cytokine expression	46
		Overventilation (ex vivo)	Inhibitor	Attenuated filtration coefficients in isolated lungs	55
		Overventilation (in vivo)	Inhibitor	Diminished IL-6 and CXCL2 release	54
		HCl lung instillation (in vivo)	Inhibitor	Reduced neutrophil recruitment to lungs	60
	COPD	IL-1β-induced mucin secretion (in vitro)	Inhibitor	Attenuated mucin secretion in cultured airway epithelial cells	95
		Chemotaxis assay (in vitro)	Inhibitor	Inhibited chemotactic responses to a CXCR3 ligand in cultured airway epithelial cells	138
		Nicotine-induced survival and transformed phenotype (in vitro)	Inhibitor	Prevented transformed phenotype and enhanced survival in human airway epithelial cells	87
	Asthma	IL-13-induced mucus secretory phenotype (in vitro)	Inhibitor	Reduced mucus hypersecretory phenotype and goblet cell metaplasia in bronchial epithelial cell cultures	88
		Thrombin-, EGF-induced and PDGF-induced (in vitro)	Inhibitor	Reduced proliferation of cultured airway smooth muscle cells	101, 102, 104
		Long-term serum deprivation (in vitro)	Inhibitor	Inhibited the transformation of cultured airway myocytes into a contractile phenotype	96
		Methacoline-induced (in vitro)	Inhibitor	Partially attenuated contraction in cultured airway smooth muscle strips	99
		Ovalbumin-induced (in vitro)	Inhibitor	Decreased bronchial contraction in isolated bronchial tissue	98
		Ovalbumin-induced (in vivo)	Inhibitor	Diminished levels of interleukins (4, 5 and 13), lung tissue eosinophilia, airway mucus production and AHR	71, 72
		Ovalbumin-induced (in vivo)	Inhibitor	No improvement in lung eosinophilia or in AHR to acetylcholine, attenuated eosinophil levels and degranulation in BAL fluid, and AHR to histamine	78, 80
p85α	ALI-ARDS	TNF-α-induced (in vitro)	Blocking protein (TAT construct)	Attenuated reactive oxygen species production in primary granulocytes	59
		TNF-α-induced (in vivo)	Blocking protein (TAT construct)	Reduced microvascular injury and granulocyte recruitment to the lung	59
	Asthma	Ovalbumin-induced (in vivo)	Gene disruption	Decreased secretion of interleukins (4 and 5), eosinophil and lymphocyte lung infiltration, and AHR	73
p110	Asthma	Thrombin-, EGF-induced (in vitro)	Gene disruption	Attenuated proliferation of cultured airway smooth muscle cells	106
p110δ	ALI-ARDS	i.p. E. coli challenge (in vivo)	Gene disruption	No protection against disease model	61
		Endotoxin-Induced (in vivo)	Inhibitor	Reduced lung neutrophil accumulation	39, 46
		Endotoxin-Induced (in vivo)	Gene disruption	Diminished neutrophils recruitment, pulmonary levels of IL-1β and TNF-α	46
		Endotoxin-Induced (in vivo)	Gene disruption	Reduced neutrophil recruitment	43
	COPD	Intranasal chemokine instillation (in vivo)	Gene disruption	No protection against disease model	67
	Asthma	Allergen-IgE-induced (in vitro)	Gene disruption and inhibitor	Inhibited degranulation and cytokine release in cultured mast cells	28
		Ovalbumin-induced (in vivo)	Inhibitor	Diminished levels of interleukins (4, 5 and 13), leucocyte infiltration to the lungs, and IgE and LTC4 release	74
		Ovalbumin-induced (in vivo)	Haemopoietic cell-restricted gene disruption	Reduced levels of type 2 cytokines, eosinophil recruitment to the lung, airway inflammation and mucus production	75
p110γ	ALI-ARDS	Overventilation (ex vivo)	Gene disruption	Attenuated levels of histological indices and levels of PKB phosphorylation in isolated lungs	56
		Endotoxin-induced (in vivo)	Gene disruption	Decreased neutrophil recruitment to the lung	43
	COPD	Chemotaxis assay (in vitro)	Gene disruption	Reduced chemotaxis to CXCR2 ligands in neutrophils	67
		Intranasal chemokine instillation (in vivo)	Gene disruption	Diminished neutrophil accumulation in the lung	67
	Asthma	Allergen-IgE-adenosine- induced (in vitro)	Gene disruption	Partially attenuated degranulation and cytokine release in cultured mast cells	29

AHR, airway hyperresponsiveness; ALI-ARDS, acute lung injury–adult respiratory distress syndrome; BAL, bronchoalveolar lavage; COPD, chronic obstructive pulmonary disease; EGF, epidermal growth factor; IgE, immunoglobulin E; IL-6, interleukin-6; LTC4, leukotriene C4; PDGF, platelet-derived growth factor; TNF-α, tumour necrosis factor-α.