TABLE 1.

Potential targets for endothelial cell dysfunction therapy

						Clinical trials
Potential target	Mechanism	Compound	Effects	In vitro	In vivo	I	II	III	IV	Ref
Inhibit NET formation	PAD4 inhibitor	Cl‐amidine	Effectively prevent the NET formation and improve overall survival in a murine sepsis model							[ 127 ]
		GSK484	Cause a dramatic reduction in thrombus deposition in mouse lungs							[ 128 ]
	TLR4 inhibitor	C34	Reduce systemic inflammation in the mouse models of endotoxemia							[ 132 ]
		TAK‐242	Suppress inflammation by combining with cysteine 747 existing in the TIR domain of TLR4, but fail to reduce cytokine levels in patients with sepsis							[ 134 , 135 ]
		Eritoran	Inhibit LPS‐induced NF‐κB activation and inflammatory cytokine production in vitro and animal models, but do not reduce 28‐mortality among patients with severe sepsis							[ 136 , 137 , 138 ]
	Degrade DNA	DNase1	Preferentially cleave protein‐free DNA and degrade the scaffold of NET structures							[ 143 ]
		DNase1‐like 3	Preferentially cleave DNA‐protein complexes and degrade the scaffold of NET structures							[ 143 ]
	NET‐inhibitory factor	nNIF and NRPs	Block NET formation in vitro and mouse models of infection and systemic inflammation, and show improved prognosis in these models							[ 144 ]
Inhibit excessive glycolysis	PFKFB3 blockade	3PO	Protect mice from acute lung injury via suppression of NF‐κB‐mediated vascular inflammation							[ 77 ]
		PFK158	Suppress ATP production and proliferation in the mouse models of small cell lung cancer							[ 149 ]
		Phenoxyindole 44	A novel inhibitor of PFKFB3 with higher selectivity							[ 150 ]
Maintenance of the balance between ROS production and clearance	Antioxidant	GSH/NAC	Remarkably decrease ROS production when the cells were exposed to plasma from septic shock patients, impair NET formation in vitro and in vivo, contribute to shorter stays in ICU and improved severity scores							[ 153 , 154 , 155 , 156 ]
		HSA	Reduce ROS and RNS production in vitro and in vivo, reverse sepsis‐induced hypotension in clinical trials							[ 157 , 158 ]
		Vitamin C	Scavenge ROS and RNS, prevent NOX activation, and decrease expression of iNOS, but do not obviously improve organ dysfunction scores or change markers of vascular damage and inflammation among patients with sepsis							[ 159 –162]

The green box denotes “Yes” and the red box denotes “No”.