The heme oxygenases, which consist of constitutive and inducible isozymes (HO-1, HO-2), catalyze the rate-limiting step in the metabolic conversion of heme to the bile pigments (i.e., biliverdin and bilirubin) and thus constitute a major intracellular source of iron and carbon monoxide (CO). In recent years, endogenously produced CO has been shown to possess intriguing signaling properties affecting numerous critical cellular functions including but not limited to inflammation, cellular proliferation, and apoptotic cell death. The era of gaseous molecules in biomedical research and human diseases initiated with the discovery that the endothelial cell-derived relaxing factor was identical to the gaseous molecule nitric oxide (NO). The discovery that endogenously produced gaseous molecules such as NO and now CO can impart potent physiological and biological effector functions truly represented a paradigm shift and unraveled new avenues of intense investigations. This review covers the molecular and biochemical characterization of HOs, with a discussion on the mechanisms of signal transduction and gene regulation that mediate the induction of HO-1 by environmental stress. Furthermore, the current understanding of the functional significance of HO shall be discussed from the perspective of each of the metabolic by-products, with a special emphasis on CO. Finally, this presentation aspires to lay a foundation for potential future clinical applications of these systems.

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Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications.

Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.

Regulation of lung injury and repair by Toll-like receptors and hyaluronan.

Hyperbaric oxygen — 100 percent oxygen at two to three times the atmospheric pressure at sea level — can result in arterial oxygen tension in excess of 2000 mm Hg1 and oxygen tension in tissue of almost 400 mm Hg.2,3 Such doses of oxygen have a number of beneficial biochemical, cellular, and physiologic effects, and today there are 259 hyperbaric facilities in the United States with 344 single-occupant (“monoplace”) hyperbaric-oxygen chambers.4 In this article, we review the mechanisms of action, evidence of clinical efficacy, and risks of therapy with hyperbaric oxygen. Physiologic Effects For hyperbaric oxygen, pressure is expressed . . .

Hyperbaric-Oxygen Therapy

The lungs of rats exposed to 100 % O2 until death and to 85 % O2 for as long as 14 days were studied using morphometric and biochemical techniques. The primary injury leading to death in rats exposed to 100 % O2 was injury to the pulmonary capillary endothelium, where 44 % of the endothelial cells were destroyed; there was a corresponding decrease in capillary surface area and in capillary lumen volume. Animals exposed to 85 % O2 had proliferation and hypertrophy of alveolar Type II epithelial cells. In addition, 41 % of the capillary endothelial cells were destroyed, but the endothelial cells that survived 7 days in 85 % O2 were hypertrophied, and after this point no further destruction of the pulmonary capillary bed took place. Exposures to 85 % O2 led to enhanced activity of the copper-zinc and manganese superoxide dismutases, which might be related to the apparently adaptive structural changes that occurred in the alveolar Type II epithelium and in the capillary endothelial cells.

Structural and biochemical changes in rat lungs occurring during exposures to lethal and adaptive doses of oxygen.

NRF2 is a transcription factor important in the protection against carcinogenesis and oxidative stress through antioxidant response element (ARE)-mediated transcriptional activation of several phase 2 detoxifying and antioxidant enzymes. This study was designed to determine the role of NRF2 in the pathogenesis of hyperoxic lung injury by comparing pulmonary responses to 95-98% oxygen between mice with site-directed mutation of the gene for NRF2 (Nrf2-/-) and wild-type mice (Nrf2+/+). Pulmonary hyperpermeability, macrophage inflammation, and epithelial injury in Nrf2-/- mice were 7.6-fold, 47%, and 43% greater, respectively, compared with Nrf2+/+ mice after 72 h hyperoxia exposure. Hyperoxia markedly elevated the expression of NRF2 mRNA and DNA-binding activity of NRF2 in the lungs of Nrf2+/+ mice. mRNA expression for ARE- responsive lung antioxidant and phase 2 enzymes was evaluated in both genotypes of mice to identify potential downstream molecular mechanisms of NRF2 in hyperoxic lung responses. Hyperoxia-induced mRNA levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione-S-transferase (GST)-Ya and -Yc subunits, UDP glycosyl transferase (UGT), glutathione peroxidase-2 (GPx2), and heme oxygenase-1 (HO-1) were significantly lower in Nrf2-/- mice compared with Nrf2+/+ mice. Consistent with differential mRNA expression, NQO1 and total GST activities were significantly lower in Nrf2-/- mice compared with Nrf2+/+ mice after hyperoxia. Results demonstrated that NRF2 has a significant protective role against pulmonary hyperoxic injury in mice, possibly through transcriptional activation of lung antioxidant defense enzymes.

https://www.atsjournals.org/doi/pdf/10.1165/ajrcmb.26.2.4501

J. M. Clark

Papers

Pulmonary oxygen toxicity: a review