Role of Pulmonary Artery Reactivity and Nitric Oxide in Injury and Inflammation Following Lung Contusion

Abstract

Rationale The mechanisms contributing to hypoxia in lung contusion remain unclear and not temporally associated with the peak onset of acute inflammation. Objective We investigated the role of oxidative stress in alteration of pulmonary arterial (PA) reactivity following LC. Additionally, the role of antioxidants in reversing this process was examined. Methods PaO2 and PA reactivity were measured in rats subjected to bilateral LC. Rings were pretreated with a NO synthase (NOS) inhibitor, L-nitro arginine (LNA 10−3 M) or PEG-superoxide dismutase (SOD) and PEG-catalase (CAT) or both (LNA+SOD/CAT). Rings were constricted with norepinephrine (NE) and relaxed with an NOS agonist (A23187) or NO donor (SNAP). Immunochemical and mass spectrometric quantification for nitrotyrosine were performed. Results Rats were hypoxemic at 4h post-contusion compared to controls, but recovered by 24h (PaO2/FiO2 ratio: baseline- 443±28, 4h-288±46 and 24h-417±23). PA constriction to NOS inhibition and relaxation to A23187 were impaired 4h after LC. PA relaxation to SNAP was decreased at 4h and 24h after LC. These alterations in PA reactivity were reversed by SOD/CAT pretreatment. SOD1 and 2 mRNA was up-regulated and soluble guanylyl cyclase (sGC) mRNA was down-regulated 24h after LC. IHC and mass spectrometry revealed that levels of 3-nitrotyrosine were increased markedly at 4h following LC consistent with superoxide generation and formation of peroxynitrite. Conclusion Collectively, this data suggests that consumption of NO due to excess superoxide resulting in peroxynitrite formation leads to diminished vascular reactivity following LC.

Physiological and Immune-Biological Characterization of a Long-Term Murine Model of Blunt Chest Trauma

“…After reaction with the ubiquitous radical amino acid tyrosine, the product 3-nitrotyrosine is able to serve as a stable marker of both oxidative and nitrosative stress (20). We demonstrate that chest trauma led to a significant increase of 3-nitrotyrosine in the lungs of subjected animals, in good agreement with another study performed in rats (21).…”

Changes in the Concentrations of Mediators of Inflammation and Oxidative Stress in Exhaled Breath Condensate During Liver Transplantation and Their Relations With Postoperative ARDS

“…The causes of postoperative ARDS after liver transplantation include many aspects, such as fluid overload from crystalloid liquid infusion or massive transfusion, hypotension, sepsis, fast tapering of corticosteroids, gastric aspiration, reperfusion syndrome of the newly implanted liver, intestinal ischemia and reperfusion, and transfusion-related acute lung injury. 24 Consistent with the findings of some studies, [25][26][27] we believed that not only inflammation but also oxidative stress were involved in the mechanism of ARDS. Our findings also indicated higher levels of mediators of inflammation and oxidative stress in EBC, indirectly showing the key role of inflammation and oxidative stress in ARDS after liver transplantation.…”

“…It has also been suggested that the severity of ARDS could be reduced by actions on several pathways, such as inhibiting the production of oxygen free radicals (such as H 2 O 2 ) and nitrate radicals (such as NO) and reducing pulmonary oxidative damage that is accompanied by increased levels of MDA and decreased levels of SOD. 26,27 Our results demonstrated that the levels of mediators of oxidative stress detected in EBC followed the same trend as those in serum, which closely correlated with the incidence of ARDS. These results also suggest that pulmonary oxidative stress may have potentially serious consequences and that the levels of mediators of oxidative stress in EBC have the potential to predict the degree of oxidative stress in OLT patients.…”

Activation of Hypoxia-Inducible Factor-1α in Type 2 Alveolar Epithelial Cell Is a Major Driver of Acute Inflammation Following Lung Contusion*

“…Our recent study suggests that products of tyrosine oxidation are sensitive markers of oxidative injury and may play an important role in LC (11, 31). To investigate the effect of acriflavine treatment on LC-mediated oxidant production, lung samples were subjected to HPLC/MS/MS, and the levels of nitrotyrosine and dinitrotyrosine, markers of oxidant-mediated lung injury, were measured.…”

“…In its most severe forms, LC is associated with acute respiratory failure, manifesting as clinical acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), and is also an independent risk factor for ventilator-associated pneumonia (1–3). Our laboratory has previously studied the time course and pathophysiology of isolated LC induced by closed-chest blunt trauma in rodent models (rats and mice) to replicate several clinical features of LC injury (4–11). …”