Critical Role of 5-Lipoxygenase and Heme Oxygenase-1 in Wound Healing

Abstract

Lipid mediators derived from 5-lipoxygenase (5-LO) metabolism can activate both pro- and anti-inflammatory pathways, but their role in wound healing remains largely unexplored. In this study we show that 5-LO knockout (5-LO(-/-)) mice exhibited faster wound healing than wild-type (WT) animals, and exhibited upregulation of heme oxygenase-1 (HO-1). Furthermore, HO-1 inhibition in 5-LO(-/-) mice abolished the beneficial effect observed. Despite the fact that 5-LO(-/-) mice exhibited faster healing, in in vitro assays both migration and proliferation of human dermal fibroblasts (HDFs) were inhibited by the 5-LO pharmacologic inhibitor AA861. No changes were observed in the expression of fibronectin, transforming growth factor (I and III), and α-smooth muscle actin (α-SMA). Interestingly, AA861 treatment significantly decreased ROS formation by stimulated fibroblasts. Similar to 5-LO(-/-) mice, induction of HO-1, but not superoxide dismutase-2 (SOD-2), was also observed in response to 5-LO (AA861) or 5-LO activating protein (MK886) inhibitors. HO-1 induction was independent of nuclear factor (erythroid derived-2) like2 (Nrf-2), cyclooxygenase 2 (COX-2) products, or lipoxin action. Taken together, our results show that 5-LO disruption improves wound healing and alters fibroblast function by an antioxidant mechanism based on HO-1 induction. Overexpression of HO-1 in wounds may facilitate early wound resolution.

Effects of Oleo Gum Resin of Ferula assa-foetida L. on Senescence in Human Dermal Fibroblasts

“…Based on the recent findings about the roles of 5-lipoxigenase (ALOX5, 5-LO) in the activation of pro-inflammatory pathways [37], we also evaluated the expression of ALOX5 in our experiments. When the treatment dosage of asafetida was increased above 10 −7 g/mL, the expression level of ALOX5 was increased in cells, which revealed that asafetida could activate pro-inflammatory signals.…”

“…CASP3 was selected because its activation could be triggered by both extrinsic (death ligand) and intrinsic (mitochondrial) pathways [36]. ALOX5 was selected so that we could evaluate the inflammatory responses of senescent HDFs after treatment with asafetida [37]. …”

Eicosanoids in tissue repair

“…Indeed, multiple studies have implicated the 5‐LOX‐LTB 4 ‐BLT1 axis in aberrant neutrophil recruitment and impaired tissue repair in experimental models of skin wound healing. In particular, 5‐LOX deficiency or pharmacological targeting of the 5‐LOX pathway resulted in accelerated cutaneous healing, likely by reducing the production of reactive oxygen species (ROS) as well as of proinflammatory cytokines and chemokines in wounded skin . Similarly, 5‐LOX‐deficient mice and mice treated with LT‐modifying drugs were protected against acute inflammatory lung injury in a model of bacterial sepsis .…”

Eicosanoids and Keratinocytes in Wound Healing

“…Studies in 5-LOX-deficient mice showed accelerated wound healing, but the reepithelialization rates did not appear to differ between the 5-LOX and wild-type mice. 38 It is not clear whether prostanoid levels were elevated in the 5-LOX knockout mice in light of other studies that have shown shunting from the 5-LOX pathway into the COX-1/COX-2 pathway with 5-LOX inhibition. 39 Regardless, the lack of 5-LOX activity was not a detriment against wound re-epithelialization.…”