Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0032285 (pneumonia)
 54,520 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Viral pneumonias cause profound worldwide morbidity, necessitating novel strategies to prevent and treat these potentially lethal infections. Stimulation of intrinsic lung defenses via inhalation of synergistically acting Toll-like receptor (TLR) agonists protects mice broadly against pneumonia, including otherwise-lethal viral infections, providing a potential opportunity to mitigate infectious threats. As intact lung epithelial TLR signaling is required for the inducible resistance and as these cells are the principal targets of many respiratory viruses, the capacity of lung epithelial cells to be therapeutically manipulated to function as autonomous antiviral effectors was investigated. Our work revealed that mouse and human lung epithelial cells could be stimulated to generate robust antiviral responses that both reduce viral burden and enhance survival of isolated cells and intact animals. The antiviral protection required concurrent induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase sources, although neither type I interferon enrichment nor type I interferon signaling was required for the inducible protection. Taken together, these findings establish the sufficiency of lung epithelial cells to generate therapeutically inducible antiviral responses, reveal novel antiviral roles for ROS, provide mechanistic insights into inducible resistance, and may provide an opportunity to protect patients from viral pneumonia during periods of peak vulnerability.IMPORTANCE Viruses are the most commonly identified causes of pneumonia and inflict unacceptable morbidity, despite currently available therapies. While lung epithelial cells are principal targets of respiratory viruses, they have also been recently shown to contribute importantly to therapeutically inducible antimicrobial responses. This work finds that lung cells can be stimulated to protect themselves against viral challenges, even in the absence of leukocytes, both reducing viral burden and improving survival. Further, it was found that the protection occurs via unexpected induction of reactive oxygen species (ROS) from spatially segregated sources without reliance on type I interferon signaling. Coordinated multisource ROS generation has not previously been described against viruses, nor has ROS generation been reported for epithelial cells against any pathogen. Thus, these findings extend the potential clinical applications for the strategy of inducible resistance to protect vulnerable people against viral infections and also provide new insights into the capacity of lung cells to protect against infections via novel ROS-dependent mechanisms.
 ...
PMID:Inducible Lung Epithelial Resistance Requires Multisource Reactive Oxygen Species Generation To Protect against Viral Infections. 3094 Jul 7

Pneumonia remains a global health threat, in part due to expanding categories of susceptible individuals and increasing prevalence of antibiotic resistant pathogens. However, therapeutic stimulation of the lungs' mucosal defenses by inhaled exposure to a synergistic combination of Toll-like receptor (TLR) agonists known as Pam2-ODN promotes mouse survival of pneumonia caused by a wide array of pathogens. This inducible resistance to pneumonia relies on intact lung epithelial TLR signaling, and inducible protection against viral pathogens has recently been shown to require increased production of epithelial reactive oxygen species (ROS) from multiple epithelial ROS generators. To determine whether similar mechanisms contribute to inducible antibacterial responses, the current work investigates the role of ROS in therapeutically-stimulated protection against Pseudomonas aerugnosa challenges. Inhaled Pam2-ODN treatment one day before infection prevented hemorrhagic lung cytotoxicity and mouse death in a manner that correlated with reduction in bacterial burden. The bacterial killing effect of Pam2-ODN was recapitulated in isolated mouse and human lung epithelial cells, and the protection correlated with inducible epithelial generation of ROS. Scavenging or targeted blockade of ROS production from either dual oxidase or mitochondrial sources resulted in near complete loss of Pam2-ODN-induced bacterial killing, whereas deficiency of induced antimicrobial peptides had little effect. These findings support a central role for multisource epithelial ROS in inducible resistance against a bacterial pathogen and provide mechanistic insights into means to protect vulnerable patients against lethal infections.
 ...
PMID:Inducible lung epithelial resistance requires multisource reactive oxygen species generation to protect against bacterial infections. 3079 56

Radiation-induced lung injury is one of the most prominent factors that interfere with chest cancer radiotherapy, and poses a great threat to patients exposed to total body irradiation. Upregulation of pro-oxidant enzymes is one of the main mechanisms through which the late effects of ionizing radiation on lung injury can be exerted. Interleukin (IL)-4 and IL-13 are two important cytokines that have been proposed to be involved in this process. Through stimulation of dual oxidase 1 and 2 (DUOX 1 & 2), they induce chronic oxidative stress in irradiated tissues. In this study, we evaluated the effects of curcumin treatment on the regulation of IL-4 and IL-13, DUOX1 & 2 genes as well as the pathological changes developed by this treatment. Twenty male Wistar rats were divided into four groups: radiation only; curcumin only; radiation +curcumin; and control group with neither pharmacotherapy nor radiation. Curcumin was administered for 4 and 6 consecutive days before and after irradiation, respectively. Also, the chest area was irradiated with 15 Gy using a cobalt-60 gamma rays source. All rats were sacrificed 67 days after irradiation, followed by the assessment of the levels of IL-4 and IL-13; the expression of IL- 4 receptor-a1 (IL4Ra1), IL13Ra2, DUOX1 and DUOX2, and finally the histopathological changes were evaluated. Radiation led to the increased level of IL-4, while the level of IL-13 showed no change. QPCR results showed the upregulation of IL4Ra1, DUOX1 and DUOX2 following lung irradiation. Histopathological evaluation also showed a remarkable increase in pneumonitis and fibrosis. Treatment with curcumin downregulated the expression of IL-4, IL4Ra1, DUOX1 & 2. Furthermore, it could mitigate pneumonitis and fibrosis following lung irradiation. The late effects of radiation- induced lung injury may be due to the upregulation of DUOX1 & 2 genes. Curcumin, through modulation of these genes, may contribute to the protection against ionizing radiation.
 ...
PMID:Curcumin Mitigates Radiation-induced Lung Pneumonitis and Fibrosis in Rats. 3151 80