Regulatory Effects of iNOS on Acute Lung Inflammatory Responses in Mice (original) (raw)
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Nitric oxide downregulates lung macrophage inflammatory cytokine production
The Annals of Thoracic Surgery, 1998
Background. Inflammatory cytokine production contributes to lung injury after lung ischemia reperfusion and during lung transplant rejection. Although nitric oxide has been demonstrated to reduce lung injury associated with the adult respiratory distress syndrome, it remains unknown whether the mechanism of nitric oxide's beneficial effects involves reducing lung macrophage inflammatory cytokine production. The purpose of this study was to determine whether nitric oxide downregulates lung macrophage inflammatory cytokine production.
Lung sources and cytokine requirements for in vivo expression of inducible nitric oxide synthase
American Journal of Respiratory Cell and Molecular Biology, 1995
Products of inducible nitric oxide synthase (iNOS) are known to be involved in lung injury following intrapulmonary deposition of immunoglobulin G immune complexes (IgG-ICx). In the current studies rat alveolar macrophages stimulated in vitro with murine interferon')' (IFN-')'), tumor necrosis factor a, interleukin Io , (IL-la) , lipopolysaccharide (LPS), or IgG-ICx immunostained for iNOS and produced nitrite/nitrate-(N02-INO)-) in a dose-and time-dependent manner requiring availability of L-arginine. Under the same conditions, IL-4 and IL-I0 reduced N0 2-INO}-generation. Type II alveolar epithelial cells, which were obtained from normal rat lungs and stimulated in vitro with IgG-ICx, LPS, or IFN-')', also immunostained for iNOS and generated N0 2-INO}-. Special techniques of bronchoalveolar lavage (BAL) were used to retrieve alveolar macrophages and type II alveolar epithelial cells. Under these conditions, intrapulmonary deposition of LPS yielded BAL fluids containing increased amounts of N0 2-I NO}-and macrophages that spontaneously released N0 2-INO}-and stained for iNOS. After intrapulmonary deposition of IgG both macrophages as well as type II cells (retrieved by BAL) spontaneously produced N0 2-INO}-and both cell types immunostained for iNOS (approximately 20 % of all type II cells and 35 %of all alveolar macrophages). Using dual fluorescence staining for cell identification, frozen sections of lung tissue after IgG immune complex deposition revealed iNOS in both alveolar macrophages and type II cells. Finally, in the immune complex model of alveolitis, the appearance of iNOS in macrophages as well as macrophage production in vitro of N0 2-INO}-was dependent on the in vivo availability of tumor necrosis factor a, ILl , and IFN-')'. These studies suggest a dual cell source for nitric oxide in inflamed lungs and the requirements for iNOS of several cytokines. Although there is abundant evidence that the pathogenesis of immunoglobulin G immune complex (IgG-ICx)-induced tissue injury requires the role of complement, the participation of phagocytic cells (neutrophils and macrophages) and products from L-arginine oxidation produced by nitric oxide synthase (NOS), precise events that can be linked to the causation of injury, are not clearly defined. It has been postulated that the influx and activation of phagocytic cells result in the local generation of toxic oxygen products (0 2-, H 202 , hydroxyl radical, and hypochlorous acid), toxic products of
Antiinflammatory effect of inhaled nitric oxide on acute lung injury
Despite no reported survival benefit by inhaled nitric oxide (NO) among patients with acute respiratory distress syndrome (ARDS) until now, NO inhalation is still deemed acceptable as a rescue therapy for ARDS patients with refractory hypoxemia to various therapeutic measures. However, it is unclear whether inhaled NO exerts either detrimental or beneficial effects on the pathogenesis of ARDS. Laboratory studies suggest that inhaled NO might reduce some types of acute lung injury (ALI). By contrast, NO and nitrite could interact with neutrophil myeloperoxidase or high oxygen in the alveoli to stimulate oxidative reactions during inflammation. Recent experimental data suggest that inhaled NO might attenuate endotoxin-induced ALI. Considering the diverse role of NO as an important endogenous regulatory molecule on both proinflammatory and antiinflammatory processes, the effects of early and continued therapy with low dose of inhaled NO on ALT should be determined.
Critical Care, 2008
Introduction Inhaled nitric oxide (INO) allows selective pulmonary vasodilation in acute respiratory distress syndrome and improves PaO 2 by redistribution of pulmonary blood flow towards better ventilated parenchyma. One-third of patients are nonresponders to INO, however, and it is difficult to predict who will respond. The aim of the present study was to identify, within a panel of inflammatory mediators released during endotoxininduced lung injury, specific mediators that are associated with a PaO 2 response to INO.
PloS one, 2015
Lipopolysaccharide (LPS) derived from the outer membrane of gram-negative bacteria induces acute lung injury (ALI) in mice. This injury is associated with lung edema, inflammation, diffuse alveolar damage, and severe respiratory insufficiency. We have previously reported that LPS-mediated nitric oxide synthase (NOS) uncoupling, through increases in asymmetric dimethylarginine (ADMA), plays an important role in the development of ALI through the generation of reactive oxygen and nitrogen species. Therefore, the focus of this study was to determine whether mice deficient in endothelial NOS (eNOS-/-) are protected against ALI. In both wild-type and eNOS-/- mice, ALI was induced by the intratracheal instillation of LPS (2 mg/kg). After 24 hours, we found that eNOS-/-mice were protected against the LPS mediated increase in inflammatory cell infiltration, inflammatory cytokine production, and lung injury. In addition, LPS exposed eNOS-/- mice had increased oxygen saturation and improved l...
Laboratory Investigation, 2002
Nitric oxide (NO) produced by NO synthase (NOS) serves as a ubiquitous mediator molecule involved in many physiologic lung functions, including regulation of vascular and bronchial tone, immunocompetence, and neuronal signaling. On the other hand, excessive and inappropriate NO synthesis in inflammation and sepsis has been implicated in vascular abnormalities and cell injury. At least three different NOS isoforms (neuronal/brain [bNOS], inducible [iNOS], and endothelial [eNOS]) have been described, which are all expressed in normal lung tissue. We investigated the cell-specific expression of bNOS, iNOS, and eNOS in perfused control rat lungs and lungs undergoing stimulation with endotoxin in the presence and absence of plasma constituents. Lung immunohistochemistry and quantitative evaluation of staining intensity showed endotoxininduced increase in iNOS expression in particular in bronchial epithelial cells, cells of the bronchus-associated lymphoid tissue (BALT), alveolar macrophages, and vascular smooth muscle cells in a time-and dose-dependent fashion. In endothelial cells, which did not express iNOS at baseline, newly induced iNOS was found in response to endotoxin. In contrast, expression of eNOS was markedly suppressed under endotoxin challenge, particularly in bronchial epithelium, BALT, and alveolar macrophages but also in vascular smooth muscle cells and endothelial cells. eNOS expression in bronchial smooth muscle cells was not altered. In contrast to iNOS and eNOS, cellular expression of bNOS in epithelial cells, nerve fibers, BALT, and endothelial cells did not change in response to endotoxin. All changes in NOS regulation were found to be independent of plasma constituents. We conclude that endotoxin exerts a profound impact on the cell-specific NOS regulation in a large number of lung cell types. Prominent features include de novo synthesis or up-regulation of iNOS, in contrast to down-regulation of eNOS, which may well contribute to vascular abnormalities, inflammatory sequelae, and loss of physiologic functions in septic lung failure. (Lab Invest 2002, 82:425-441).
Respiratory Physiology & Neurobiology, 2009
cal evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, which were reduced by 1400W treatment. Behavioural stress in sensitised animals amplified the resistance and elastance responses after antigen challenge, numbers of eosinophils and iNOS+ cells, actin content and 8-iso-PGF2 ␣ density in the distal lung compared to the OVA group. 1400W treatment in ovalbumin-exposed and stressed animals reduced lung mechanics, iNOS+ cell numbers and 8-iso-PGF2 ␣ density compared to sensitised and stressed animals that received vehicle treatment. We concluded that stress amplifies the distal lung constriction, eosinophilic inflammation, iNOS expression, actin content and oxidative stress previously induced by chronic lung inflammation. iNOS-derived NO contributes to stress-augmented lung tissue functional alterations in this animal model and is at least partially due to activation of the oxidative stress pathway.
Respiratory Care, 2012
To analyze the early effects of low INO dose on oxygenation, oxidative stress, inflammatory, and histopathological lung injury in a rabbit model of acute lung injury (ALI). METHODS: This was a prospective, controlled, in vivo animal laboratory study. Forty rabbits were instrumented and ventilated at F IO 2 1.0. ALI was induced by tracheal infusion of warm saline (30 mL/kg, 38°C) and lung oxidative stress was assessed by total antioxidant performance (TAP) assay. Animals were assigned to groups: control group (no. ؍ 10, low tidal volume [V T ] ؍ 6 mL/kg, PEEP ؍ 5 cm H 2 O), ALI without INO (no-INO group, no. ؍ 10, low V T ؍ 6 mL/kg, PEEP ؍ 10 cm H 2 O), ALI plus INO (INO group, no. ؍ 10, low V T ؍ 6 mL/kg, PEEP ؍ 10 cm H 2 O, INO ؍ 5 ppm). Plateau pressure was limited to 30 cm H 2 O in all groups. Ten non-instrumented animals (healthy group) were studied for TAP assay. Ventilatory and hemodynamic parameters were recorded every 30 min for 4 hours. RESULTS: After lung injury, the instrumented groups were worse than the control group for P aO 2 (control group 438 ؎ 87 mm Hg, no-INO group 80 ؎ 13 mm Hg, INO group 81 ؎ 24 mm Hg, P < .001). The INO group showed decreased lung inflammation by leukocyte count in lung lavage fluid (no-INO group 4.8 ؎ 1.64, control group 0.16 ؎ 0.15, INO group 0.96 ؎ 0.35 polymorphonuclear cells ؋ 10 6 /bronchoalveolar lavage fluid/lung, P < .001), decreased histopathological injury score (no-INO group 5 [range 1-16], INO group 2 [range 0 -5], control group 0 [range 0 -3], P < .001), and better lung protection against oxidative injury than the no-INO group (healthy group 68 ؎ 8.7, control group 66.4 ؎ 6.8, INO group 56.3 ؎ 5.1, no-INO group 45.9 ؎ 3.4 percent protection/g protein, P < .001). CONCLUSIONS: INO attenuates oxidative stress and histopathological and inflammatory lung injury in a saline-lavaged rabbit ALI model. Key words: ARDS; mechanical ventilation; oxidative injury; acute lung injury; rabbits; inhaled nitric oxide. [Respir Care 2012;57(2): 273-281.
CHEST Journal, 2004
Terada, Lance S., Nancy N. Mahr, and Eugene D. Jacobson. Nitric oxide decreases lung injury after intestinal ischemia. J. Appl. Physiol. 81(6): 2456-2460.-After injury to a primary organ, mediators are released into the circulation and may initiate inflammation of remote organs. We hypothesized that the local production of nitric oxide (NO) may act to limit the spread of inflammation to secondarily targeted organs. In anesthetized rats, 30 min of intestinal ischemia followed by 2 h of reperfusion (I/R) did not increase lung albumin leak. However, after treatment with N G -nitro-Larginine methyl ester (L-NAME), intestinal I/R led to increased lung leak, suggesting a protective effect of endogenous NO. The site of action of NO appeared to be the lung and not the gut because 1) after treatment with L-NAME, local delivery of NO to the lung by inhalation abolished the increase in intestinal I/R-induced lung leak; 2) L-NAME had no effect on epithelial permeability ( 51 Cr-labeled EDTA clearance) of reperfused small bowel; and 3) after treatment with L-NAME, local delivery of NO to the gut by luminal perfusion did not improve epithelial permeability of reperfused intestines. Furthermore, L-NAME increased, and inhaled NO decreased, the density of lung neutrophils in rats subjected to intestinal I/R, and treatment with the selectin antagonist fucoidan abolished L-NAME-induced lung leak in rats subjected to intestinal I/R. We conclude that endogenous lung NO limits secondary lung injury after intestinal I/R by decreasing pulmonary neutrophil retention.