Figure 3.

Therapeutic strategies are involved in heme metabolic pathway. strategies include extracellular and intracellular ways. Extracellular mechanisms mainly conclude scavenger proteins haptoglobin (Hp)/hemopexin (Hx) binding hemoglobin (Hb)/free heme respectively. Furthermore, albumin binds free heme inhibiting its proinflammatory effects. Hp-Hb complex binds to CD163 receptor expressed on the cell membrane, leading to endocytosis and degradation of the Hb and Hp complexes. It is noteworthy that CO binding Fe²⁺ in hemoproteins could prevent heme releasing. Heme-Hx complex is recognized by cell receptor CD91, delivering heme for catabolism by HO-1. The intracellular heme is degraded by HO-1. In addition, cellular heme levels could be excluded by heme efflux transporters FLVCR and Bcrp/Abcg2. Gene therapy and HO-1 inducers could regulate HO-1. HO-1 inducers contain natural (polyphenols) and synthetic (DMF) compounds. In addition, as the substrate of HO-1, hemin is a natural HO-1 inducer existing in human body. The labile ferrous iron released from heme catabolism is subsequently sequestered by ferritin, thus conferring cyto-protection against heme-Fe²⁺. The end products of HO-1 activity, namely BV/BR, and CO act as pharmacologic molecules. CO could be elevated by inhalation or through the use of CO-releasing molecules (CORMs). Additional therapy involving CO includes CO-binding hemoglobins. BV/BR treatment and BVR expression is also proposed as intervention strategies.