Extracellular hemoglobin, a byproduct of hemolysis, can release its prosthetic heme groups upon oxidation. Blood plasma contains proteins that scavenge heme. It is estimated that about 2–8% of the heme released in plasma becomes ‘bioavailable’, being internalized by bystander cells. If the heme degradation capacity of a cell, represented by heme oxidase 1 and 2, cannot be ramped up sufficiently then heme signaling and reactivity puts cells under stress. Platelets are activated by heme, and macrophages switch to the inflammatory type (Donegan et al, 2019; Gouveia et al, 2019).

Free (labile) heme accumulates in the blood stream in great amounts under pathological conditions like viral infections and malaria, but also ARDS amd COPD. The locally affected cells' primary reaction is to upregulate heme oxidase 1 (HMOX1) expression. HMOX1 induction in these cells not only removes heme from circulation but also triggers a functional switch toward the anti-inflammatory phenotype (Vijayan et al, 2018). However, heme scavenging and degradation systems may get overwhelmed by the sheer amount of heme present.

Heme promotes platelet activation, complement activation, vasculitis, and thrombosis (Bourne et al, 2020; Merle et al, 2018). Heme was recognized to act as a danger signal, damage-associated molecular pattern (DAMP), or alarmin (Soares and Bozza, 2016) and was shown to activate Toll-like receptor 4 (TLR4) signaling (Figueiredo et al, 2007; Janciauskiene et al, 2020). It also has a role as corepressor in the circadian clock system (Ko and Takahashi, 2006). BACH1 is regulated by heme in a cell, thus placing heme as a signaling molecule in gene expression in higher eukaryotes. The regulation of BACH1 by heme may be important for the stress response in general (Suzuki et al, 2004).

Extracellular hemoglobin, a byproduct of hemolysis, can release its prosthetic heme groups uponoxidation. Due to the reactive nature of free heme, the blood plasma contains proteins that scavenge heme. It is estimated that about 2–8% of the heme released in plasma becomes ‘bioavailable’, being internalized by bystander cells. Failure of nearby cells to sufficientlymetabolize free heme can incite platelet activation, macrophage differentiation, and oxidative stress (Donegan et al, 2019; Gouveia et al, 2019).