Toxic oxygen free radicals have been implicated as important pathologic mediators in many clinical disorders. We discuss the chemistry of oxygen radical production and the roles of iron an...

Oxygen Radicals and Human Disease

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.

The importance of free radicals and catalytic metal ions in human diseases

Background Infectious diseases may rival cancer, heart disease, and chronic lung disease as sources of morbidity and mortality from smoking. We reviewed mechanisms by which smoking increases the risk of infection and the epidemiology of smoking-related infection, and delineated implications of this increased risk of infection among cigarette smokers. Methods The MEDLINE database was searched for articles on the mechanisms and epidemiology of smoking-related infectious diseases. English-language articles and selected cross-references were included. Results Mechanisms by which smoking increases the risk of infections include structural changes in the respiratory tract and a decrease in immune response. Cigarette smoking is a substantial risk factor for important bacterial and viral infections. For example, smokers incur a 2- to 4-fold increased risk of invasive pneumococcal disease. Influenza risk is severalfold higher and is much more severe in smokers than nonsmokers. Perhaps the greatest public health impact of smoking on infection is the increased risk of tuberculosis, a particular problem in underdeveloped countries where smoking rates are increasing rapidly. Conclusions The clinical implications of our findings include emphasizing the importance of smoking cessation as part of the therapeutic plan for people with serious infectious diseases or periodontitis, and individuals who have positive results of tuberculin skin tests. Controlling exposure to secondhand cigarette smoke in children is important to reduce the risks of meningococcal disease and otitis media, and in adults to reduce the risk of influenza and meningococcal disease. Other recommendations include pneumococcal and influenza vaccine in all smokers and acyclovir treatment for varicella in smokers.

https://jamanetwork.com/journals/jamainternalmedicine/articlepdf/217624/ira30766.pdf

Cigarette smoking and infection.

Activated alveolar macrophages and epithelial type II cells release both nitric oxide and superoxide which react at near diffusion-limited rate (6.7 x 10(9) M-1s-1) to form peroxynitrite, a potent oxidant capable of damaging the alveolar epithelium and pulmonary surfactant. Peroxynitrite, but not nitric oxide or superoxide, readily nitrates phenolic rings including tyrosine. We quantified the presence of nitrotyrosine in the lungs of patients with the adult respiratory distress syndrome (ARDS) and in the lungs of rats exposed to hyperoxia (100% O2 for 60 h) using quantitative immunofluorescence. Fresh frozen or paraffin-embedded lung sections were incubated with a polyclonal antibody to nitrotyrosine, followed by goat anti-rabbit IgG coupled to rhodamine. Sections from patients with ARDS (n = 5), or from rats exposed to hyperoxia (n = 4), exhibited a twofold increase of specific binding over controls. This binding was blocked by the addition of an excess amount of nitrotyrosine and was absent when the nitrotyrosine antibody was replaced with nonimmune IgG. In additional experiments we demonstrated nitrotyrosine formation in rat lung sections incubated in vitro with peroxynitrite, but not nitric oxide or reactive oxygen species. These data suggest that toxic levels of peroxynitrite may be formed in the lungs of patients with acute lung injury.

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Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury.

Monoclonal antibodies OKT3 (all T cells), OKT4 (T-helper/inducer), and OKT8 (T-suppressor/cytotoxic) were used to determine surface phenotypes of bronchoalveolar lavage and peripheral blood lymphocytes in patients with chronic hypersensitivity pneumonitis. Similar studies were done in asymptomatic pigeon breeders, patients with sarcoidosis, and nonsmoking controls. Increased numbers of lavage T cells were found in patients with hypersensitivity pneumonitis and sarcoidosis and in asymptomatic pigeon breeders. The predominant T-cell subset in patients with hypersensitivity pneumonitis and in asymptomatic pigeon breeders was T8 +; in contrast, the predominant subset in those with sarcoidosis was T4 +. Peripheral blood T-cell subsets were normal in all groups. Thus, most lung T lymphocytes in chronic hypersensitivity pneumonitis belong to the T8 + subset; the local cellular immune response in hypersensitivity pneumonitis and sarcoidosis are different; and the pattern of alveolitis, as determined by bronchoalveolar lavage, is not the sole determinant of lung impairment after exposure to hypersensitivity pneumonitis antigens.

Lung T cells in hypersensitivity pneumonitis

Intact erythrocytes placed into the tracheobronchial tree of hyperoxic rats dramatically improved their chances for survival. Over 70 percent of the animals so treated survived more than 12 days during continuous exposure to 95 percent oxygen, whereas all of the control animals died within 96 hours. Lungs from erythrocyte-protected rats showed almost none of the morphologic damage suffered by untreated animals. Erythrocytes containing cyanomethemoglobin were as beneficial as normal erythrocytes, but cells in which glutathione was partially blocked were significantly less protective. Analogous results were obtained in vitro: 51Cr-labeled target cells released 70 to 90 percent of their label when exposed briefly to hydrogen peroxide or to toxic oxygen species generated by phorbol ester-stimulated neutrophils. Addition of intact erythrocytes decreased release by approximately 75 percent, but significantly less than this if red blood cell glutathione was partially blocked. These results suggest that insufflated erythrocytes, through their recyclable glutathione, protect rats from toxic oxygen species engendered by hyperoxia.

https://science.sciencemag.org/content/sci/227/4688/756.full.pdf

Protection against lethal hyperoxia by tracheal insufflation of erythrocytes: role of red cell glutathione

To test the feasibility of using liposomes to deliver therapeutic agents to the lungs, the effect of liposome-encapsulated superoxide dismutase (SOD) or catalase on pulmonary oxygen toxicity was studied in rats. The SOD or catalase was encapsulated in negatively changed multilamellar liposomes and administered directly into the trachea of adult rats, which were subsequently exposed to hyperoxia (greater than 95% O2). Response to hyperoxia was examined by studying lung SOD and catalase activities, survival rates, and lung morphology. Rats receiving liposome-encapsulated SOD or catalase showed increased levels of enzyme activities in the lung homogenates compared with those in the control groups after 24 to 72 h of hyperoxic exposure. Elevated enzyme levels in the lungs of rats treated with liposome-encapsulated SOD or catalase were accompanied by a significant improvement in survival rates after 72 h of hyperoxic exposure and less lung injury than in the other control groups.

Protection against pulmonary oxygen toxicity in rats by the intratracheal administration of liposome-encapsulated superoxide dismutase or catalase.

The polymorphonuclear leukocyte (PMN) may play an important role in the pathogenesis of emphysema Cigarette smoking is associated with the accumulation of PMN in the lung as determined by bronchoalveolar lavage We enumerated alveolar wall PMN on histologic sections from lungs of humans and hamsters with and without cigarette smoke exposure In human nonsmokers, there were 09 +/- 02 PMN/mm alveolar wall In cigarette smokers without emphysema, there were 21 +/- 03 PMN/mm alveolar wall (p less than 001), and in cigarette smokers with emphysema, there were 24 +/- 07 PMN/alveolar wall (p less than 005) There were 17 +/- 03 PMN/mm alveolar wall in the lungs of hamsters unexposed to cigarette smoke compared with 31 +/- 03 PMN/mm alveolar wall in smoke-exposed hamsters (p less than 0005) Although cigarette smoking causes PMN to accumulate within alveolar septa, the accumulation does not seem to be closely related to the development of emphysema This suggests that additional or other factors are important in the pathogenesis of emphysema

Cigarette smoking causes accumulation of polymorphonuclear leukocytes in alveolar septum.

Hyperoxia-mediated pulmonary damage may involve formation of toxic oxygen species such as superoxide, hydrogen peroxide, and hydroxyl radical. Intact red cells evidently scavenge these when insufflated in small numbers into the tracheobronchial tree of rats. Such manipulation protects hyperoxic rats for prolonged periods of time and preserves normal pulmonary histology. Of several potential oxygen metabolite scavengers, a role for red cell glutathione seems particularly likely. It has not escaped our attention that an ironic, and previously unsuspected, connotation of our results emerges: namely, that a small degree of spontaneous alveolar bleeding, which is not an uncommon feature in respiratory distress situations, may actually be beneficial to patients--particularly those ventilated with excessive inspired oxygen concentrations. If confirmatory studies from other laboratories are forthcoming, the tracheal insufflation of autologous red cells in ventilated patients might be considered in the future.

Bruce A. Schwartz

Papers

Lung T cells in hypersensitivity pneumonitis

Protection against lethal hyperoxia by tracheal insufflation of erythrocytes: role of red cell glutathione

Protection against pulmonary oxygen toxicity in rats by the intratracheal administration of liposome-encapsulated superoxide dismutase or catalase.

Cigarette smoking causes accumulation of polymorphonuclear leukocytes in alveolar septum.

Insufflated red cells protect lungs from hyperoxic damage: role of red cell glutathione in scavenging toxic O2 radicals.