geranylgeranylacetone and Inflammation

Fibrosis is a response to ongoing cellular injury, disruption, and tissue remodeling, the pathogenesis of which is unknown, and is characterized by extracellular matrix deposition. The antifibrotic effect of Geranylgeranylacetone (GGA), as an inducer of Heat shock protein 70 (HSP70), in liver, kidney and pulmonary fibrosis has been supported by multiple preclinical evidence. However, despite advances in our understanding, the precise roles of HSP70 in fibrosis require further investigation. The purpose of this study was to investigate whether GGA could participate in the progression of pulmonary fibrosis in mice through apoptosis, oxidative stress and inflammation.. B-cell lymphoma-2(Bcl-2) and Bcl2-Associated X (Bax) are two proteins related to apoptosis. Anti-apoptotic factor Bcl-2 and pro-apoptotic factor Bax are often involved in the apoptotic process in the form of dimer. Immunofluorescence and Western blot results showed that bleomycin (BLM) and transforming growth factor-β (TGF-β) inhibited Bcl-2 expression and promoted Bax expression in vitro and in vivo, respectively. In contrast, GGA treatment reverses this change. Reactive oxygen species (ROS), Malondialdehyde (MDA) and superoxide dismutase (SOD) are markers of oxidative stress, which often reflect oxidative injury of cells. The detection of ROS, MDA and SOD expression showed that TGF-β and BLM treatment could significantly promote oxidative stress, while GGA treatment could alleviate oxidative stress damage. In addition, BLM significantly elevated Tumor necrosis factor-α(TNF-α), Interleukin1β (IL-1β) and Interleukin 6 (IL-6), while scutellarin reversed the above alterations except for that of GGA.. Taken together, GGA suppressed apoptotic, oxidative stress and inflammation in BLM-induced pulmonary fibrosis.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Bleomycin; Fibrosis; Inflammation; Lung; Mice; Oxidative Stress; Pneumonia; Pulmonary Fibrosis; Reactive Oxygen Species; Superoxide Dismutase; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha

Heat shock transcription factor 1 (HSF1) is a master regulator of heat shock response, and also inhibits expression of inflammatory cytokines directly or indirectly. Here, we examined effects of HSF1 activation on the expression of proinflammatory cytokines in mouse cochlea after exposure to noise.. Male CBA/N mice with normal Preyer's reflex were exposed to intense noise for 3h. Three hours after noise exposure, bilateral cochleae were removed and expression of major inflammatory cytokines was examined.. We found that interleukin-6 (IL-6) and interleukin-1β (IL-1β) expression increased significantly after noise exposure, and the expression was suppressed significantly in mice administered with geranylgeranylacetone (GGA), which activates HSF1. Seven days after noise exposure, thresholds for auditory brainstem response were elevated, and GGA administration significantly suppressed this elevation.. These results suggest that HSF1-mediated suppression of proinflammatory cytokines in the cochlea by GGA administration could be an important means of inner ear protection.

Topics: Animals; Auditory Threshold; Cochlea; Cytokines; Diterpenes; DNA-Binding Proteins; Evoked Potentials, Auditory, Brain Stem; Hearing Loss, Noise-Induced; Heat Shock Transcription Factors; Inflammation; Interleukin-1beta; Interleukin-6; Male; Mice; Mice, Inbred CBA; Noise; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factors

Geranylgeranylacetone, an acyclic isoprenoid, is a non-toxic inducer of heat shock protein (HSP)70. HSP70 overproduction is associated with heat tolerance in rats. This study aimed to investigate whether geranylgeranylacetone preconditioning of rats reduced heat-induced inflammation and multiple organ dysfunction.. Anaesthetised rats were given vehicle or geranylgeranylacetone (800 mg/kg) orally. After 48 h they were exposed to ambient temperature of 43 degrees C for 70 min to induce heatstroke. Another group of rats kept at room temperature were used as normothermic controls.. Vehicle-treated rats all succumbed to heat stress; their survival time was 25 +/- 4 min. Pretreatment with geranylgeranylacetone significantly increased survival time to 92 +/- 15 min. Compared with normothermic controls, all vehicle-treated heatstroke rats displayed hepatic and renal dysfunction (e.g. increased plasma levels of serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase) and active inflammation (e.g. increased plasma and brain levels of interleukin-1 beta, tumour necrosis factor-alpha and interleukin-6). These heat-stress response indicators were all significantly suppressed by geranylgeranylacetone pretreatment. In addition, the plasma and brain levels of interleukin-10 (an anti-inflammatory cytokine) and brain levels of HSP70 were significantly increased after geranylgeranylacetone preconditioning during heatstroke.. Geranylgeranylacetone preconditioning attenuates heat-induced inflammation and multiorgan dysfunction in rats.

Topics: Animals; Brain; Diterpenes; Heat Stroke; Hot Temperature; HSP70 Heat-Shock Proteins; Inflammation; Interleukin-10; Interleukin-1beta; Interleukin-6; Male; Multiple Organ Failure; Rats; Rats, Wistar; Survival; Time Factors; Tumor Necrosis Factor-alpha

We investigated whether an acyclic polyisoprenoid antiulcer drug, geranylgeranylacetone (GGA), induces the expression of HSP70 in the rat cochlea. Immunoblotting revealed upregulation of HSP70 in the cochlea at 12 h after transtympanic (local) or oral (systemic) administration of GGA, and this increased at 24 h after administration. Positive immunohistochemical staining of HSP70 was observed in the hair cells, the spiral ganglion, the stria vascularis, the spiral ligament, and the perivascular portion of modiolar vessels. We therefore subsequently studied the effects of GGA as an HSP-inducer on inner ear trauma due to inflammation. Damage to the lateral wall due to inflammation induced by lipopolysaccharide inoculation was protected against by pretreatment with GGA, as assessed physiologically by measurement of cochlear blood flow and morphologically by electron microscopy. The results of the present study suggest that GGA can protect the cochlea against other injuries including those induced by noise, ototoxic drugs, and ischemia by upregulating HSP70.

Topics: Animals; Anti-Ulcer Agents; Cochlea; Diterpenes; Escherichia coli; Female; Hearing Loss, Sensorineural; HSP70 Heat-Shock Proteins; Immunoblotting; Immunohistochemistry; Inflammation; Lipopolysaccharides; Microscopy, Electron; Multivariate Analysis; Rats; Rats, Sprague-Dawley; Spiral Ganglion; Stria Vascularis; Up-Regulation

The present study was performed to determine whether oral pretreatment with geranylgeranylacetone (GGA) inhibits proinflammatory cytokine liberation and nitric oxide (NO) production in lipopolysaccharide (LPS)-treated rats and protects rats against death from LPS-induced endotoxin shock, and whether such protection by GGA is related to heat shock protein (HSP) 70 induction in multiple organs of rats. GGA (200 mg/kg) was given orally to rats. LPS (20 mg/kg) was administered intraperitoneally 4, 8, 16, or 24 h after GGA administration. The survival of rats was monitored over 24 h after LPS administration. GGA treatment at 8 or 16 h before LPS dramatically improved the survival rate of LPS-treated rats. Plasma levels of proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) and NO 6 h after LPS administration in these GGA-pretreated rats were less than one-half of those in rats treated with LPS alone. A GGA challenge 8 or 16 h before LPS administration enhanced HSP70 expression in rat organs after LPS. Treatment with GGA 8 h before LPS minimized hepatic and renal damage. Furthermore, the protective effect of GGA on mortality in LPS-treated rats was inhibited with quercetin, known as an HSP70 inhibitor. These results suggest that oral administration of GGA at an optimal time before LPS injection induces and enhances HSP70 expression in several organs, inhibits proinflammatory cytokine and NO production, and prevents organ damage, resulting in an improved survival rate.

Topics: Administration, Oral; Animals; Anti-Ulcer Agents; Blotting, Western; Disease Models, Animal; Diterpenes; Dose-Response Relationship, Drug; Endotoxins; HSP70 Heat-Shock Proteins; Inflammation; Interleukin-6; Kidney; Lipopolysaccharides; Male; Nitric Oxide; Rats; Rats, Sprague-Dawley; Shock; Time Factors; Treatment Outcome; Tumor Necrosis Factor-alpha