The Biology and Function of Tissue Inhibitor of Metalloproteinase 2 in the Lungs

Table 1

Known functions of TIMP2 and corresponding-associated diseases.

Functions	Diseases	Mechanism	Reference
Protooncogene induction	Asthma exacerbations; Lung cancer	TIMP2 enhances c-fos expression; c-fos increased in lungs of asthmatic rats.	[14, 101]
Pro-MMP-2 activation	Squamous cell lung carcinoma	c-SRC tyrosine kinase induced pro-MMP-2 activation in the presence of MMP-14; MMP-2 found in high concentrations in SCLC.	[28]
Cell proliferation and inhibition of angiogenesis	Various types of lung cancers	Inhibition of VEGF-A and FGF-2 in vitro and in vivo. TIMP2 can bind α3β1 integrin heterodimer and stimulate SHP1-mediated dephosphorylation of FGFR1 or EGFR.	[70, 73, 82, 83]
Matrix stability and lung remodeling	IPF	TIMP2 colocalizes with Ki67+fibroblasts in IPF lungs; TIMP2 observed along with MMP1, 2, and 9 in regenerated epithelial cells covering intra-alveolar fibrosis.	[93, 94]
Inhibition of apoptosis	COPD	TIMP2 may inhibit apoptosis of macrophages and foam cells in airway epithelial cells, leading to decreased inflammation.	[88]
Extracellular matrix deposition	Acute lung injury	Bleomycin induces expression of TIMP2 in interstitial compartments.	[90, 92]
Antiaging	Dementia	Age-related decline in TIMP2 protein is observed in hippocampal lysates, neurons of the subgranular zone, and hilar areas of dentate gyrus of mice.	[14, 15]
	Tendinopathy	Age-dependent reduction of TIMP2 expression in rabbit patellar tendons	[130]
Anti-inflammatory	Systemic inflammatory response syndrome; Neuroinflammatory disorders	TNFα/IL1β regulate TIMP2 expression in cardiac cells; inhibition of TIMP2 in microglial cells increase cytokine production. TIMP2 suppresses microglial activation through regulation of Nrf2 and cAMP-response element binding protein transcription factors.	[22, 69, 70]