Heme oxygenase-1 (HO-1) is regarded as a sensitive and reliable indicator of cellular oxidative stress. Studies on carbon monoxide (CO) and bilirubin, two of the three (iron is the third) end products of heme degradation have improved the understanding of the protective role of HO against oxidative injury. CO is a vasoactive molecule and bilirubin is an antioxidant, and an increase in their production through an increase in HO activity assists other antioxidant systems in attenuating the overall production of reactive oxygen species (ROS), thus facilitating cellular resistance to oxidative injury. Gene transfer is used to insert specific genes into cells that are either otherwise deficient in or that underexpress the gene. Successful HO gene transfer requires two essential elements to produce functional HO activity. Firstly, the HO gene must be delivered in a safe vector, e.g., adenoviral, retroviral or leptosome based vectors, currently being used in clinical trials. Secondly, with the exception of HO gene delivery to either ocular or cardiovascular tissue via catheter-based delivery systems, HO delivery must be site and organ specific. This has been achieved in rabbit ocular tissues, rat liver, kidney and vasculature, SHR kidney, and endothelial cells [Abraham et al., 1995a; Abraham et al., 1995b; Abraham et al., 2002c; Quan et al., 2004; Sabaawy et al., 2000; Sabaawy et al., 2001; Yang et al., 2004]. In this review, we discuss the functional significance of the HO system in various pathophysiological conditions and the beneficial therapeutic applications of human HO gene transfer and gene therapy in a variety of clinical circumstances.
Risk factors for cardiovascular diseases include hyperglycemia, TNF, and reactive oxygen species (ROS), which collectively contribute to vascular endothelial cell dysfunction and apoptosis. We examined, in vascular endothelial cells, whether the selective expression of heme oxygenase-1 (HO-1) offers cytoprotection against glucose- and TNF-mediated cell death. An adenoviral vector expressing human HO-1 was constructed using a VE-cadherin (VECAD) promotor fragment, and cell-specific expression of the recombinant adenovirus was examined using endothelial and vascular smooth muscle cells. The effects of HO-1 transduction (Ad-VECAD-HO-1 gene) on HO-1 expression, HO activity, and the response to TNF and hyperglycemia were studied. Human HO-1 gene was selectively expressed in endothelial cells after infection with the Ad-VECAD-HO-1 vector. Selective expression of HO-1 prevented TNF- and hyperglycemia-mediated superoxide (O2-) formation, DNA degeneration, and upregulation of caspase, but increased the expression of pAkt and Bcl-xL, proteins responsible for endothelial dysfunction in diabetes. These results demonstrate that endothelial cell survival after oxidative stress injury may be enhanced by targeting HO-1 expression, thus blocking inflammation, apoptosis, and thereby attenuating cardiovascular risk factors.
Mycobacterium gordonae is a slow-growing mycobacterium that is the least pathogenic of the mycobacteria. Infection with M. gordonae is most commonly reported in immunocompromised patients. We present a rare case of M. gordonae infection in an immunocompetent individual. A 37-year-old woman was found to have a pulmonary nodule in the left upper lobe. The patient denied any respiratory symptoms, including cough, sputum production, fever, chest pain, or shortness of breath. The patient was a lifetime nonsmoker. Physical examination was normal. Computed tomography (CT) scan of the chest revealed several discrete pleural-based inflammatory infiltrates bilaterally. The patient was treated with oral amoxicillin-clavulinic acid initially and a repeat CT scan chest was scheduled after 2 weeks. Laboratory data were nonsignificant. Repeat CT scan did not show any resolution. Patient positron emission tomography scan revealed marked hypermetabolic uptake involving bilateral parenchymal nodules, mediastinal lymph nodes, and the spleen. A thoracotomy with biopsy of the left upper lobe nodule revealed necrotizing granulomatous pneumonitis with rare acid-fast bacilli. Cultures were positive for M. gordonae. The patient was started on a multidrug regimen of azithromycin, rifampin, and ciprofloxacin, based on drug sensitivities, for 12 months. Repeat CT scan and positron emission tomography scan after treatment showed complete resolution. The patient has remained disease-free 5 years after treatment. Instead of always dismissing M. gordonae as a contaminant, we should include it in our differential diagnosis of pulmonary infection in both immunocompetent and immunocompromised hosts. Further studies are needed to understand the pathogenesis of M. gordonae infection in humans.
The incidental detection of solitary pulmonary nodules and ground-glass nodules has increased substantially with the use of computed tomography as a diagnostic modality and is expected to rise exponentially as lung cancer screening guidelines are more widely implemented by primary care physicians. The lesions should then be classified as low, indeterminate, or high risk for malignancy, depending on the clinical and radiological characteristics. Once classified, these lesions should be evaluated and managed as per expert consensus-based recommendations for performing follow-up computed tomography scans and tissue sampling depending on the pretest probability. When weighing the risks and benefits of further investigations, patient preference and suitability for surgery should be taken into consideration as well.
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