Whiting C, Castillo A, Haque MZ, Majid DS. Protective role of the endothelial isoform of nitric oxide synthase in ANG IIinduced inflammatory responses in the kidney. Am J Physiol Renal Physiol 305: F1031-F1041, 2013. First published August 7, 2013 doi:10.1152/ajprenal.00024.2013In the present study, we examine the hypothesis that the nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays a protective role in the development of ANG II-induced hypertension and renal injury by minimizing oxidative stress and the inflammation induced by TNF-␣. Systolic blood pressure (SBP) and renal injury responses to chronic infusions of ANG II (via implanted minipumps) were evaluated for 2 wk in wild-type (WT) and in eNOS knockout mice (KO) cotreated with or without a superoxide (O 2 Ϫ ) scavenger, tempol (400 mg/l in the drinking water), or a TNF-␣ receptor blocker, etanercept (5 mg/kg/day ip). In study 1, when ANG II was given at a dose of 25 ng/min, it increased mean SBP in WT mice (⌬36 Ϯ 3 mmHg; n ϭ 7), and this effect was attenuated in mice pretreated with tempol (⌬24 Ϯ 3 mmHg; n ϭ 6). In KO mice (n ϭ 9), this dose of ANG II resulted in severe renal injury associated with high mortality. To avoid this high mortality in KO, study 2 was conducted with a lower dose of ANG II (10 ng/min) that increased SBP slightly in WT (⌬17 Ϯ 7 mmHg; n ϭ 6) but exaggeratedly in KO (⌬48 Ϯ 12 mmHg, n ϭ 6) associated with severe renal injury. Cotreatment with either tempol (n ϭ 6) or etanercept (n ϭ 6) ameliorated the hypertensive, as well as the renal injury responses in KO compared with WT. These data demonstrate a protective role for eNOS activity in preventing renal inflammatory injury and hypertension induced by chronic increases in ANG II. endothelial nitric oxide synthase activity; tumor necrosis factor-␣; superoxide; angiotensin II; hypertension; renal injury HYPERTENSION IS CONSIDERED to be a low-grade inflammatory condition induced by various proinflammatory cytokines including 43,44). Recent studies have implicated the involvement of TNF-␣ in the development of renal injury in hypertension induced by ANG II (12,43,44). A relationship between the renin-angiotensin system and the production of TNF-␣, and its potential role in regulating cardiovascular function are increasingly evident from the findings of many recent studies (10,18,35,49). TNF-␣ has been implicated in the development of glomerulonephritis (42) as well as saltsensitive hypertension (12) induced by ANG II. It has been observed that chronic ANG II infusion fails to cause hypertensive responses in knockout mice lacking the gene for TNF-␣ (48) or its source, T-lymphocytes (10, 18). ANG II induced up-regulation of the protein expressions of NAD(P)H oxidase enzyme subunit, gp91 phox , and endothelial nitric oxide synthase (eNOS) enzyme in the myocardium was absent in TNF-␣ gene knockout mice (49). These findings suggest an important modulatory role for this cytokine in the nitrosative and oxidative stress mechanisms induced by ANG II.Redox equilibrium is critical f...

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Stereotactic ablative radiotherapy (SABR) has become the standard of care for inoperable early-stage nonsmall cell lung cancer (NSCLC). Many patients cannot safely undergo a biopsy because of poor pulmonary function and are empirically treated with radiotherapy. This study aimed to evaluate factors associated with radiation toxicity in patients receiving empiric SABR. Methods: We performed a retrospective review of 69 patients. Patients and tumor characteristics, radiation doses, pulmonary function tests, and toxicity (acute ≤ 90 days and late > 90 days) were analyzed to find associations with overall survival on Kaplan-Meier curves and differences in patient populations with χ 2 and Mann-Whitney U tests. Results: Median age was 71 years. Tumors were classified as peripheral in 62 patients (89.9%). After a median followup of 18 months, 39 patients (56.5%) were alive with 4 local recurrences (5.7%), 10 regional failures (14.3%), and 15 distant metastases (21.4%). Nineteen of 67 (26.3%) patients had acute toxicity of which 9 had acute grade ≥ 2 toxicity. There were differences in overall survival based on operability status (P = .031) and acute toxicity (P < .001). Pretreatment oxygen dependence (P = .003), central location (P < .001), and new oxygen requirement (P = .02) were significantly associated with acute grade ≥ 2 toxicity. No association was found with performance on pulmonary function tests. Conclusion: Empiric SABR in presumed early-stage NSCLC appears to be safe and may increase overall survival. Acute grade ≥ 2 toxicity was significantly associated with pretreatment oxygen dependence, central location, and new oxygen requirement. No association was found with poor pulmonary function.