Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activating mutations in K-ras are one of the most common genetic alterations in human lung cancer. To dissect the role of K-ras activation in bronchial epithelial cells during lung tumorigenesis, we created a model of lung adenocarcinoma by generating a conditional mutant mouse with both Clara cell secretory protein (CC10)-Cre recombinase and the Lox-Stop-Lox K-ras(G12D) alleles. The activation of K-ras mutant allele in CC10 positive cells resulted in a progressive phenotype characterized by cellular atypia, adenoma and ultimately adenocarcinoma. Surprisingly, K-ras activation in the bronchiolar epithelium is associated with a robust inflammatory response characterized by an abundant infiltration of alveolar macrophages and neutrophils. These mice displayed early mortality in the setting of this pulmonary inflammatory response with a median survival of 8 weeks. Bronchoalveolar lavage fluid from these mutant mice contained the MIP-2, KC, MCP-1 and LIX chemokines that increased significantly with age. Cell lines derived from these tumors directly produced MIP-2, LIX and KC. This model demonstrates that K-ras activation in the lung induces the elaboration of inflammatory chemokines and provides an excellent means to further study the complex interactions between inflammatory cells, chemokines and tumor progression.
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PMID:K-ras activation generates an inflammatory response in lung tumors. 1628 13

In order to explore the potential mechanism that animals with cardiopulmonary diseases were more susceptible than healthy animals, the spontaneously hypertensive rats (SHR) as a model of human cardiovascular disease were used. SHR and wistar kyoto rats (WKY) were exposed by intratracheal instillation to fine particles with the doses of 0.0 (saline), 1.6, 8.0 and 40.0mg/kg body weight, respectively. The exposure was done once a day, for three continuous days. The rats were killed after 24h following the last exposure, followed by analysis of bronchoalveolar lavage fluid (BALF) to estimate the lung injury. Meantime, parameters of oxidative stress, cytokines and cell surface receptors related to inflammation and anti-inflammation were also measured. The results showed that lactate dehydrogenase (LDH) activity, percentages of neutrophils and lymphocytes, and expression of TBA-reactive substances and cytokines (IL-1beta, TNF-alpha, MIP-2, OPN, NF-kappaB, CC16 and HO-1) and cell surface receptors (CD44 and TLR-4) were increased in rats, but percentage of macrophages decreased. Meanwhile, at the same dose exposed, the levels of those parameters were higher in SHR than that in WKY rats. The results indicated that inflammation might be one of the mechanisms of lung injury induced by fine particles. Results of comparisons of different response to fine particles between SHR and WKY rats suggested that lung injury induced by fine particles was greater in SHR than that in WKY rats.
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PMID:Pulmonary responses to fine particles: differences between the spontaneously hypertensive rats and wistar kyoto rats. 1760 36

We have examined the role of NF-kappaB regulated genes in airway epithelium in mediating tobacco smoke induced airway inflammation in studies of CC10-Cre(tg)/Ikk beta(Delta/Delta) mice in which NF-kappaB signaling through I kappaB-kinase-beta (IKK-beta) is selectively ablated in epithelial cells in the airway. CC10-Cre(tg)/Ikk beta(Delta/Delta) mice exposed to tobacco smoke for seven days had a significant decrease in the number of BAL cells (total cells, neutrophils, and macrophages) as well as significantly reduced numbers of peribronchial cells (F4/80+ and myeloperoxidase+) compared to tobacco exposed WT mice. In addition to the reduction in peribronchial cells, CC10-Cre(tg)/Ikk beta(Delta/Delta) mice exposed to tobacco smoke had a significant decrease in the number of macrophages and neutrophils in the alveolar space suggesting that inactivation of NF-kappaB in the airway epithelium influenced the number of neutrophils and macrophages recruited to the alveolus. Levels of the NF-kappaB regulated chemokines KC and MCP-1 were significantly reduced in lungs of tobacco smoke exposed CC10-Cre(tg)/Ikk beta(Delta/Delta) mice compared to tobacco exposed WT mice. In contrast, there was no significant difference in levels of NF-kappaB regulated MIP-1 alpha between CC10-Cre(tg)/Ikk beta(Delta/Delta) and WT mice. Lung sections of tobacco smoke exposed CC10-Cre(tg)/Ikk beta(Delta/Delta) mice immunostained with KC or MCP-1 antibodies demonstrated reduced expression of these chemokines in the airway epithelium, but not in alveolar epithelium. Overall, these studies demonstrate an important role for NF-kappaB regulated genes in airway epithelium in contributing to acute tobacco smoke induced airway inflammation not only in the peribronchial space but also in the alveolar space.
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PMID:Inactivation of I kappaB-kinase-beta dependent genes in airway epithelium reduces tobacco smoke induced acute airway inflammation. 2049 24