Down-regulated Peroxisome Proliferator-activated Receptor γ (PPARγ) in Lung Epithelial Cells Promotes a PPARγ Agonist-reversible Proinflammatory Phenotype in Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition and a leading cause of death, with no available cure. We assessed the actions in pulmonary epithelial cells of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor with anti-inflammatory effects, whose role in COPD is largely unknown. We found that PPARγ was down-regulated in lung tissue and epithelial cells of COPD patients, via both reduced expression and phosphorylation-mediated inhibition, whereas pro-inflammatory nuclear factor-κB (NF-κB) activity was increased. Cigarette smoking is the main risk factor for COPD, and exposing airway epithelial cells to cigarette smoke extract (CSE) likewise down-regulated PPARγ and activated NF-κB. CSE also down-regulated and post-translationally inhibited the glucocorticoid receptor (GR-α) and histone deacetylase 2 (HDAC2), a corepressor important for glucocorticoid action and whose down-regulation is thought to cause glucocorticoid insensitivity in COPD. Treating epithelial cells with synthetic (rosiglitazone) or endogenous (10-nitro-oleic acid) PPARγ agonists strongly up-regulated PPARγ expression and activity, suppressed CSE-induced production and secretion of inflammatory cytokines, and reversed its activation of NF-κB by inhibiting the IκB kinase pathway and by promoting direct inhibitory binding of PPARγ to NF-κB. In contrast, PPARγ knockdown via siRNA augmented CSE-induced chemokine release and decreases in HDAC activity, suggesting a potential anti-inflammatory role of endogenous PPARγ. The results imply that down-regulation of pulmonary epithelial PPARγ by cigarette smoke promotes inflammatory pathways and diminishes glucocorticoid responsiveness, thereby contributing to COPD pathogenesis, and further suggest that PPARγ agonists may be useful for COPD treatment.     

Rapid elevations in both steroid hormones and vocal signaling during playback challenge: a field experiment in Gulf toadfish

It is well known that plasma androgens are rapidly released in response to aggressive or sexual stimuli in a broad array of vertebrates. However, experimental work on behavioral functions of rapid androgen elevation is rare. A combination of field-based behavioral experiments and lab-based neuroendocrinological approaches is beginning to show how steroid hormones rapidly regulate the expression of vocal communication signals in Gulf toadfish (Opsanus beta). Male toadfish emit multiharmonic "boatwhistles" and shorter-duration, broadband "grunts" during intraspecific communication. Neurophysiology experiments demonstrate that androgens and glucocorticoids rapidly modify vocal motor patterning in male toadfish. In this study, we simulated territorial intrusions (vocal "challenges") with acoustic playbacks to toadfish in the field, and observed simultaneous, rapid (within 5-20 min) changes in vocalizations and steroid hormones. Both plasma androgens and vocal activity increased following the presentation of pure tones that mimic the duration of natural boatwhistles (275 ms), while they remained unchanged following playbacks of tone stimuli that mimic the duration of grunts (75 ms) or the upper-range of boatwhistles (475 ms). Circulating glucocorticoids were elevated in calling vs. non-calling males but were unaffected by playback stimuli, suggesting a role in the energetics of vocalization. These results strongly suggest that one function of rapid androgen elevation in response to social challenge is to mediate similarly rapid changes in territorial vocal signaling. Given the conserved organization of neuroendocrine and vocal motor systems, rapid steroid action on vocalization mechanisms may be true of other vocal vertebrates as well, including birds and mammals.     

Biochemical and morphological attributes of broiler kidney in response to dietary glucocorticoid,dexamethasone

Glucocorticoids (GCs) initiate oxidative stress and cause renal damage which lead to hypertension, heart failure and ultimately death. The current study aimed to investigate the alterations in serum biochemical parameters i.e. HDL and LDL; gross anatomy, histomorphology and histomorphometry of broiler kidney in response to dietary GC, dexamethasone (DEX). Day old chicks (DOCs) were randomly assigned into four groups: control and three treatment groups (T1, T2 and T3). The control group was fed commercial broiler type ration and the treated groups were fed commercial broiler type ration containing GC (Dexamethasone @ 3, 5 and 7 mg/kg in T1, T2 and T3 group respectively). To measure the biochemical parameters, blood samples were collected on days 7, 14, 21, and 28 of the experiment. For histological investigation, kidney (left) samples were collected from the individual birds after sacrificing on days 7, 14, 21, and 28 of the experiment. Histomorphological alterations of the kidney were assessed by routine hematoxylin and eosin (H&E) staining. Biochemical analysis showed significantly increased serum HDL and LDL level compared to the control. In gross study, dark congested kidney was found with significantly decreased weight, length and width. Treatment with DEX augmented congestion, inflammation and fibrosis in kidney, as evidence by histomorphometric study. Extensively degenerated and atrophied glomeruli, degenerated tubular epithelium with distorted tubules and inter tubular empty spaces were seen. Percentage of atrophied glomeruli increased significantly and maximum percentage of glomerular atrophy was seen at day 28. These changes were found more explicitly in the higher dose group. Histomorphometric study also revealed significant decrease in the diameter of glomerulus. The findings of this study suggest that DEX may alter the serum biochemical parameters as well as kidney gross and histomorphology.     

The discovery of potent and selective non-steroidal glucocorticoid receptor modulators,suitable for inhalation

We report the discovery of highly potent and selective non-steroidal glucocorticoid receptor modulators with PK properties suitable for inhalation. A high throughput screen of the AstraZeneca compound collection identified sulfonamide 3 as a potent non-steroidal glucocorticoid receptor ligand. Further optimization of this lead generated indazoles 30 and 48 that were progressed to characterization in in vivo models. X-ray crystallography was used to gain further insight into the binding mode of selected ligands.