Septic shock and cardiovascular dysfunction (e.g., hemorrhagic shock) are leading causes of death in the intensive care unit (ICU). Activation of neutrophils in response to these types of shock have been linked to the release of neutrophil extracellular traps (NETs) via a process called NETosis. NET formation is triggered by peptidylarginine deiminase (PAD), which is composed of five isozymes (PAD1, 2, 3, 4 and 6). Targeting isozymes of PAD for inhibition of NETosis could open up a new paradigm for the treatment of life-threatening sepsis and hemorrhagic shock. PAD2 and PAD4 are the most relevant isozymes that are highly expressed in neutrophils. While NETosis has traditionally been associated with PAD4, inhibition of PAD4 alone cannot reduce the inflammatory response because PAD4 deficiency induces compensational expression of PAD2 in neutrophils. Therefore, inhibition of PAD4 alone may not be sufficient and neutrophil NET formation needs to be regulated by both PAD2 and PAD4. For this reason, we seek to (1) determine whether and how PAD2 and PAD4 double knockout (DKO) or PAD2 single KO can efficiently inhibit the NETosis and improve survival in a mouse sepsis model; (2) evaluate whether blood levels of proteins (PAD2, PAD4, CitH3, PCT, IL-1β, troponin, etc.) can serve as diagnosis biomarkers in the mouse models; and (3) analyze whether and how PAD2 and PAD4 DKO or PAD2 single KO can protect against traumatic cardiovascular injury.