Hydrogen peroxide as a damage signal in tissue injury and inflammation: murderer, mediator, or messenger?

Abstract

Tissue injury and inflammation are associated with increased production of reactive oxygen species (ROS), which have the ability to induce oxidative injury to various biomolecules resulting in protein dysfunction, genetic instability, or cell death. However, recent observations indicate that formation of hydrogen peroxide (H2 O2 ) during tissue injury is also an essential feature of the ensuing wound healing response, and functions as an early damage signal to control several critical aspects of the wound healing process. Because innate oxidative wound responses must be tightly coordinated to avoid chronic inflammation or tissue injury, a more complete understanding is needed regarding the origins and dynamics of ROS production, and their critical biological targets. This prospect highlights the current experimental evidence implicating H2 O2 in early epithelial wound responses, and summarizes technical advances and approaches that may help distinguish its beneficial actions from its more deleterious actions in conditions of chronic tissue injury or inflammation.

Keywords: CELL MIGRATION; CHEMOTAXIS; CYSTEINE; NOX/DUOX; REACTIVE OXYGEN SPECIES; REDOX SIGNALING.

Figure 1. Interrelationship between Ca²⁺, ATP and H₂O₂ as early damage signals after epithelial injury

Mechanical or chemical epithelial injury results in increased intracellular Ca²⁺ through e.g. connexin channels (Cx) or transient receptor potential (TRP) channels, and thereby promoting the secretion of ATP. Extracellular ATP can activate purinergic P2Y or P2X receptor subtypes on the cell surface to stimulate Ca²⁺-dependent signaling and activation of PKC, and thereby stimulates H₂O₂ production e.g. by activating DUOX. H₂O₂ can diffuse into target cells to initiate redox signaling and can also promote Ca²⁺ influx as well as ATP efflux, further indicating the close interplay between these conserved damage signals.

Figure 2. Actions of DUOX-derived H₂O₂ in epithelial wound responses

1) DUOX-derived H₂O₂ at the luminal surface creates an H₂O₂ gradient that repels bacteria to minimize infection, and produces antimicrobial HOSCN by lactoperoxidase (LPO)-catalyzed oxidation of SCN⁻. 2) DUOX-derived H₂O₂ participates in intracellular redox signaling, e.g. through EGFR/ERK activation, and thereby regulates cytoskeletal dynamics and promotes expression of wound genes such as MMP-9, to stimulate epithelial cell migration. 3) DUOX-derived H₂O₂ promotes recruitment of neutrophils as a critical component of the wound response, by direct chemotactic properties and/or by increased production of the neutrophil chemokine IL-8.

Figure 3. Mechanisms of H₂O₂-dependent redox signaling through cysteine oxidation

H₂O₂ can oxidize select protein cysteine thiols (existing as thiolate anion due to low pK_a) to initially form sulfenic acid (RSOH), which in turn can react with either cellular GSH to form RSSG (mixed disulfide with GSH, also known as S-glutathionylation), neighboring protein cysteines to form intra- or intermolecular disulfides, or with H₂O₂/ROS to form sulfenic (RSO₂H) and sulfonic (RSO3H, not shown) acids. With the exception of RSO_2/3H, these various cysteine oxidations can be reversed by thioredoxin (Trx)/glutaredoxin (Grx) systems, thus constituting reversible H₂O₂-dependent redox signaling. In select cases, RSO₂H can be reversed back to ROH by sulfiredoxins (Srx).