Indian Journal of Pharmacology Home 

[Download PDF]
Year : 2015  |  Volume : 47  |  Issue : 2  |  Page : 153--159

Differential effects of dexamethasone and rosiglitazone in a sephadex-induced model of lung inflammation in rats: Possible role of tissue inhibitor of metalloproteinase-3

Jignesh K Nagar1, Praful P Patel2, Jogeswar N Mohapatra3, Manoranjan M Sharma3, Gaurav M Pandya4, Malik M Umar3, Abhijit A Chatterjee3, Shrikalp S Deshpande5, Mukul R Jain3, Hitesh M Soni6,  
1 Department of Pharmacology, Zydus Research Centre, Ahmedabad; Department of Pharmacology, KB Institute of Pharmaceutical Education and Research, Gandhinagar, Gujarat, India
2 Department of Toxicology, Torrent Research Center, Ahmedabad, Gujarat, India
3 Department of Pharmacology, Zydus Research Centre, Ahmedabad, Gujarat, India
4 Department of Animal Genetics and Breeding, College of Veterinary Science and Animal Husbandry, Navsari Agricultural University, Navsari, Gujarat, India
5 Department of Pharmacology, KB Institute of Pharmaceutical Education and Research, Gandhinagar, Gujarat, India
6 Department of Pharmacology, Zydus Research Centre, Ahmedabad, Gujarat, India; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA

Correspondence Address:
Hitesh M Soni
Department of Pharmacology, Zydus Research Centre, Ahmedabad, Gujarat, India; Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA


Objectives: To study the effects of two different classes of drugs in sephadex-induced lung inflammation using rats and explore the potential mechanism (s). Materials and Methods: Effects of dexamethasone (0.3 mg/kg, p.o.) and rosiglitazone (10 mg/kg, p.o.) treatments were evaluated up to 3 days in sephadex challenged rats. 72 h postsephadex administration, broncho-alveolar lavage fluid (BALF) was collected for cell count and cytokine estimation. Lung tissues were harvested for gene expression and histopathology. Results: Dexamethasone treatment resulted in significant inhibition of lymphocytes, monocytes, eosinophils and neutrophils, whereas rosiglitazone inhibited eosinophils and neutrophils only. Further, dexamethasone reduced the elevated levels of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) after sephadex challenge while rosiglitazone significantly reduced the PGE2 levels without altering LTB4 in the BALF. Hydroxyproline content in rat lung homogenate was significantly reduced with dexamethasone treatment but not with rosiglitazone. Both the drugs were found to suppress matrix metallo proteinase 9, whereas only dexamethasone showed inhibition of tumor necrosis factor-alpha and up-regulation of tissue inhibitor of metalloproteinase 3 (TIMP-3) expression and preserved the broncho-alveolar microstructure. Conclusions: Our results revealed that up-regulation of TIMP-3 corroborated well with dexamethasone mediated inhibition of collagen degradation and restoration of alveolar micro-architecture.

How to cite this article:
Nagar JK, Patel PP, Mohapatra JN, Sharma MM, Pandya GM, Umar MM, Chatterjee AA, Deshpande SS, Jain MR, Soni HM. Differential effects of dexamethasone and rosiglitazone in a sephadex-induced model of lung inflammation in rats: Possible role of tissue inhibitor of metalloproteinase-3.Indian J Pharmacol 2015;47:153-159

How to cite this URL:
Nagar JK, Patel PP, Mohapatra JN, Sharma MM, Pandya GM, Umar MM, Chatterjee AA, Deshpande SS, Jain MR, Soni HM. Differential effects of dexamethasone and rosiglitazone in a sephadex-induced model of lung inflammation in rats: Possible role of tissue inhibitor of metalloproteinase-3. Indian J Pharmacol [serial online] 2015 [cited 2021 Feb 25 ];47:153-159
Available from:

Full Text


The sephadex-induced lung inflammation in rat is a model of acute alveolitis and bronchiolitis leading to inflammatory cell infiltration and interstitial edema, which appears parallel to many of the pathophysiological features associated with human interstitial lung diseases. [1] Animal studies of sephadex-induced model clearly represent the patterns of inflammatory characteristics of asthma. [2] Matrix metallo proteinases (MMPs) are one of the major players in airway remodeling process. The MMPs are endopeptidases, which play an important role in physiologic and pathological processes including extracellular matrix (ECM) turnover, tissue degradation and repair, cell migration, and inflammation. Two the secreted MMPs, gelatinase-A (MMP-2) and gelatinase-B (MMP-9) can degrade type-IV collagen, the major collagen in all basement membranes and act on cleaved collagen better than other MMPs. [3] MMP-2 and MMP-9 are the major proteinases involved in bronchial remodeling in asthma. [4] An imbalance in the MMPs and their biologic regulators, like tissue inhibitors of metalloproteinase (TIMPs) may result in matrix degradation. The TIMPs are endogenous MMP inhibitors that regulate and maintain matrix homeostasis when present in the dynamic interstitial compartment. [5] It directly inhibits the disruptive activities of MMPs and has been implicated in the regulation of cell shape, function, and survival. Different types of TIMPs can bind and inactivate various MMPs, including MMP-2 and MMP-9, but with different affinities. Furthermore, examination of molar ratios of MMPs to TIMPs (TIMP-1 or TIMP-2) in various pathological conditions has provided insight into the importance of interrelationships between MMPs and TIMPs. Lack of TIMP-3, enhances the inflammatory response, which leads to sepsis, mechanical ventilation, hyperoxia in mice and spontaneous air space enlargement in the lungs. TIMP-3 can also inhibit MMP-2 and MMP-9. [6],[7] It has been reported that TIMP-3 has been down-regulated in the inflamed intestine of patients with Crohn's disease. [8] However, role of TIMP-3 is not clear in the animal model of asthma. The use of anti-inflammatory drugs that reduce MMPs and increase TIMP-3 may be effective against airways remodeling due to acute lung inflammation.

Although sephadex model is extremely rapid and simple, limited information underlying cellular and molecular mechanisms are available. We hypothesized that the MMPs/TIMPs system may be closely involved in granuloma formation in the sephadex model. Therefore, our aim was to study the effect (s) of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and glucocorticoid receptor (GR) agonist in a sephadex-induced lung inflammation model in rat and correlate it with the regulation of MMPs and TIMPs.

 Materials and Methods


Rosiglitazone was obtained from Cadila Healthcare Ltd., Ahmedabad, India. Sephadex; G-200 superfine, dexamethasone and other reagent were obtained from Sigma Aldrich Co., USA.


Male Wistar rats of 6-8 weeks of old were purchased from the Jackson Laboratory. Rats were housed in individual ventilated cages and given pelleted food (Lab Diet, Purina Mills, India) and water ad libitum in a temperature (25°C) and humidity (45-55%) controlled environment with a 12 h/12 h dark-light cycle. The study was approved by the Institutional Animal Ethics Committee. The experimental procedures were performed in accordance with the guidelines of the committee for the purpose of control and supervision of experiment on animals, India.

Experimental Design

Sephadex G-200 beads (0.5 mg/ml) were suspended in normal saline and soaked at 4°C for 72 h after autoclaving. Animals received 1 ml of sephadex suspension intravenously via the tail vein where as normal control rats received saline only. One hour prior to the sephadex injection, dexamethasone (0.3 mg/kg) and rosiglitazone (10 mg/kg) suspended in 0.5% methylcellulose was administered by oral gavages followed by two subsequent doses in 24 h intervals. We have used six animals in each group.

Differential Leucocyte Counts in Broncho-alveolar Lavage Fluid

Rats were administered an overdose of pentobarbital sodium (120 mg/kg i.p.) on day 4. After semi-excision of the trachea, a plastic cannula was inserted, and airspaces were washed with 5 mL of heparin (6 IU/mL) treated saline. After 2 min, the lavage fluid was recovered by gentle aspiration. This operation was repeated 2 more times, and collections were pooled. The fluid phase of the first milliliter of broncho-alveolar lavage fluid (BALF) was centrifuged (4000 rpm for 10 min, 4°C) and the supernatant was frozen at −80°C until cytokine analysis. Remaining pooled portion of BALF was centrifuged (600 g for 10 min, 4°C) and the supernatant fraction discarded and the cells pellet re-suspended in 1 mL of saline. Total white blood cells (WBCs) were counted by coulter counter method using Cell-DYN 3700 (Abbott instruments, USA). A small piece of lower right lung was snap frozen in liquid nitrogen for gene expression and the estimation of hydroxyproline. Rest of the tissue was fixed in 10% formal saline for histological examination.

Broncho-alveolar Lavage Fluid Cytokines Measurement

The concentration of tumor necrosis factor-alpha (TNF-α) in BALF was measured using a commercially available enzyme-linked immuno sorbent assay (ELISA) kit (BD Biosciences, San Diego, USA). Levels of leukotriene B4 (LTB4) and prostaglandin E2 (PGE2) were also measured using specific ELISA kits (R and D systems, Inc., Minneapolis, USA).

Histopathological Analysis

Tissue sections were prepared of the lungs tissues fixed immediately in 10% formal saline. Paraffin-embedded sections (4 μm) of the lung were stained with hemotoxylin-eosin and masson's trichrome stain. The lung histology was assessed by light microscopy.

Gene Expression using Quantitative Reverse Transcription Polymerase Chain Reaction

Lung tissue samples were homogenized in trizol reagent (Invitrogen, Life Technologies, Carlsbad, CA, USA) using a Polytron hand-held homogenizer (Kinemitica, Switzerland) and total RNA was extracted following the manufacturer's protocol. Quality and quantity of RNA samples were assessed by spectrophotometric analysis. 1 μg of total RNA from each sample was taken for first-strand cDNA synthesis using a high-capacity cDNA reverse transcription kit (Applied Biosystems, Foster City, CA, USA).An equal amount of cDNA from each sample was taken for quantitative reverse transcription polymerase chain reaction (qRT-PCR) using 2 × fast SYBR green master mixes (QIAGEN) using ABI7300 system. PCR was conducted to amplify target cDNA fragments for MMP-9 and TIMP-3. Primers for MMP-9 and TIMP-3, listed in [Table 1], were design from rat sequences. Housekeeping gene ribosomal acidic protein was used with both the genes for normalization of the results. Melting curve analysis was carried out at the end of the qRT-PCR.{Table 1}

Hydroxyproline Assay

Quantitative hydroxyproline assay of lungs was performed at the end of the experiment as an indicator of collagen content. A modification of previously described method was utilized. [9]

Statistical Analysis

Results are expressed as mean ± standard error of the mean. Data were analyzed by one-way ANOVA followed by Tukey's multiple comparison tests. All analysis was done using GraphPad Prism software version 5.0 (GraphPad Software Inc., La Jolla, CA, USA). P <0.05 was considered to be statistically significant.


Sephadex Challenge Mediates Changes in Cellular Composition in Broncho-alveolar Lavage Fluid

Intravenously injected sephadex led to a significant increase in the WBCs count (neutrophil, eosinophil, monocyte, lymphocyte), compared with saline treated rats. Treatment of rats with rosiglitazone (10 mg/kg, p.o.) or dexamethasone (0.3 mg/kg, p.o.) produced inhibition of the total number of cells in the BALF of sephadex challenged group. Dexamethasone treatment resulted in a significant (P < 0.05) inhibition of the total WBCs count, whereas rosiglitazone was less effective and inhibited only the eosinophils and neutrophils [Table 2].{Table 2}

Alteration of Cytokine and Prostaglandins in Broncho-alveolar Lavage Fluid after Sephadex Challenge

Level of TNF-α in the BALF was increased significantly (P < 0.05) after intravenous (i.v) injection of sephadex as compared to saline challenged animals (25.55 ± 2.9 vs. 5.81 ± 0.9 pg/mL). Oral administration of dexamethasone (0.3 mg/kg) showed significant (P < 0.01) reduction in TNF-α level, which was lowered to 7.46 ± 0.6 pg/mL in the BALF after 3 days treatment whereas rosiglitazone had no effect [Figure 1]a. BALF LTB4 levels were also significantly increased (P < 0.05) in sephadex treated animals when compared with saline treated group (91.75 ± 15.9 vs. 14.4 ± 1.8 pg/mL). Oral administration of only dexamethasone showed significant (P < 0.05) reduction in LTB4 levels, which was lowered to 49.12 ± 4.5 pg/mL, whereas rosiglitazone treatment has no significant effect [Figure 1]b. In this study, we found that there was significant (P < 0.01) elevation of PGE2 levels in sephadex injected animals in the BALF as compared to saline control animals (5508.0 ± 442.8 vs. 155 ± 55.5 pg/mL, P < 0.05). There was a significant reduction in PGE2 (452 ± 75.2 vs. 5508.0 ± 442.8 pg/mL, P < 0.05) in the rosiglitazone treated group as compared to sephadex control animals. Interestingly, 90% inhibition of PGE2 was observed in rosiglitazone treated group whereas dexamethasone treatment showed almost 59% inhibition (2255 ± 555 vs. 5508 ± 442.8 pg/mL, P < 0.05) [Figure 1]c.{Figure 1}

Histopathological Examination of Lung

Haemotoxylin-eosin stained tissues of sephadex treated rats showed prominent inflammation by infiltration of inflammatory cells around the small vessels and interstitium along with mild interstitial edema. More inflammatory cells were present in the alveolar spaces and infiltrated in the alveolar septa and expanded them. In the rosiglitazone treated animals, a few cells were present in the edematous alveolar spaces where as in dexamethasone treated group lower amounts of inflammatory cell recruitment was observed in the broncho-alveolar spaces [Figure 2]. Based on these results we determined the collagen degradation by sephadex using Masson's trichrome staining. As an indicator of fibrosis, immature collagen fibers, which appeared green in Masson's trichrome stain, began to deposit focally around the arterioles, bronchioles and alveolar septae in sephadex challenged animals. We found mild collagen deposition around the basement membrane and less subepithelial fibrosis in the rosiglitazone treated group. However, dexamethasone treatment elegantly maintained the lung integrity or bronchial tissue connectivity that might be due to inhibition of collagen degradation [Figure 2].{Figure 2}

Expression of Matrix Metalloproteinase 9 and Tissue Inhibitor of Metalloproteinase 3 in the Lung Tissue

Intravenous administration of sephadex caused up-regulation of MMP-9 expression in lungs which was found to be 3.39 ± 0.19 fold as compared to saline control group. However, we couldn't find any difference in MMP-2 expression between the sephadex challenged and normal control animals (data not shown). For the 1 st time we demonstrated down regulation of TIMP-3 (0.28 ± 0.06 fold) in sephadex-induced lung inflammation model. Among the two classes of drugs, dexamethasone significantly (P < 0.05) inhibited the MMP-9 level and up regulated the TIMP-3 expression in lung tissue. Rosiglitazone showed reduction in MMP-9 level, but did not show significant effects on TIMP-3 expression in lung tissue after normalization with the housekeeping gene ribosomal acidic protein [Figure 3]a and b.{Figure 3}

Sephadex Results in Increased Matrix Hydroxyproline Deposition

Hydroxyproline content in lung homogenates from mice was utilized as an index of matrix collagen content [Figure 4]. Sephadex-induced remodeling was associated with a significant increase in hydroxyproline (P < 0.05) when compared to normal mice. Hydroxyproline content was reduced significantly in dexamethasone treated animals whereas it was unaltered by rosiglitazone group when compared with sephadex control animals.{Figure 4}


Corticosteroids are till date the most effective anti-inflammatory medications for the treatment of asthma. Several studies have demonstrated the beneficial effect of glucocorticoids (GCs) in asthma by reducing subepithelial collagen deposition in lung tissues by maintaining the balance between MMPs and TIMP-1. [10] However, major side-effects of steroids limit their therapeutic usefulness. [11] PPAR-gamma a different class of drug may be a substitute for steroids and has been shown to play an important role in the control of inflammatory responses, including within the lung, acting on both immune and nonimmune cells and may help overcome the steroid mediated side effects. PPARs are a member of the nuclear hormone receptor comprises four sub-types: PPAR-alpha, PPAR-beta, PPAR-gamma, and PPAR-delta. PPAR-gamma is highly expressed in white adipose tissue with lower levels in skeletal muscle and liver. It has also been reported that PPAR-gamma expression is increased in asthmatic airways. [12] Bronchial biopsies of untreated asthmatics have considerably more PPAR-gamma staining than nonasthmatic tissue, particularly in mucosal eosinophils and macrophages, airway smooth muscle, and epithelial cells. [13] There is now evidence that activation of PPAR-gamma may regulate ECM deposition that occurs in the airway wall remodelling. The antifibrotic effect of ciglitazone seen in vivo may also be related to regulation of the activity of MMPs or their inhibitors. It has previously been reported that rosiglitazone, a specific PPAR-gamma agonist, inhibits MMP-9 expression in bronchial epithelial cell lines. [14],[15] In vivo studies have shown that PPAR-gamma activators and GC agonists can inhibit the release of inflammatory cytokines from airway epithelial cells. [16] Given the growing evidence of the anti-inflammatory effect of these agents, it is speculated that there may also be promising anti-remodelling actions. The current study investigates the anti-remodeling effect of rosiglitazone and dexamethasone in a model of sephadex-induced lung inflammation in rat. Our findings are similar to several earlier studies demonstrating marked accumulation of eosinophils and neutrophils in the airways and BALF. [17] Surprisingly, we found that a single i.v administration of sephadex was sufficient to elicit early changes in airway remodeling. The most striking change in the model was an increase in subepithelial collagen deposition, as determined by morphometric analysis of Masson's trichrome-stained lung tissue sections and total lung collagen measured by the hydroxyproline analysis. Deposition of collagen in the airway is a key feature of airway remodeling. Our study showed that collagen deposition was associated with up-regulation of MMP-9 and down regulation of TIMP-3 expression in the lung tissues postsephadex challenge. These data demonstrated that both airway inflammation and airway fibrosis occurred in response to sephadex.

In the present study, we have evaluated two different treatment regimens, PPAR-gamma ligand rosiglitazone and GR agonist dexamethasone and have observed very distinct effects in the lung inflammation model. Treatment with rosiglitazone caused a marked reduction in eosinophils and neutrophils, which are complemented by earlier data demonstrating that rosiglitazone caused reduction in eosinophils and neutrophils in BALF in ovalbumin induced asthma model. [18] However, potent GR agonist dexamethasone produced a characteristically different response and suppressed lymphocytes and monocytes in addition to eosinophils and neutrophils. TNF-α levels are increased in several other inflammatory diseases including asthma and chronic obstructive pulmonary diseases. Previously it has also been demonstrated that sephadex particles increased TNF-α expression in lung epithelial cells and in the BALF. [19] In the present study, treatment with dexamethasone but not rosiglitazone showed reduction of TNF-α in BALF. This effect on TNF-α specifically by dexamethasone might be related to its inhibitory effect on lymphocyte and monocytes infiltration into the alveolar compartment.

In the current study we have also measured PGE2 and LTB4 levels in the BALF from sephadex treated rats, since these PGs have been postulated to have a role in animal model of antigen-induced inflammation and in the inflammatory lung disease. Interestingly for the 1 st time we have demonstrated a marked increase in PGE2 levels in the BALF after sephadex challenge. PGE2 plays a key role in numerous physiological and pathophysiological settings as inflammation, and it induces constriction and relaxation of smooth muscles on vascular and nonvascular tissues. [20],[21] The increase in PGE2 level may be one possible explanation for the increased airway hyperresponsiveness due to sephadex. This prostanoid is known to modulate the immune response by regulating the function of cells such as macrophages, T and B lymphocytes. LTB4 also stimulates leukocyte migration, aggregation, adhesion, oxidative burst activity, and degranulation. [22] In the current study, dexamethasone reduced the elevated levels of both PGE2 and LTB4 postsephadex challenge while rosiglitazone treatment was more selective and significantly attenuated the PGE2 levels without altering LTB4 in the BALF. Previously, Hazra et al. also reported a decrease in PGE2 in response to rosiglitazone and pioglitazone. [23] Decrease in cytokine and PGs by the drug treatments may prevent further infiltration of neutrophils and other proinflammatory cells to the site of injury.

Histopathological findings also revealed distinct difference in rosiglitazone and dexamethasone treatment groups. Rosiglitazone treatment reduced the inflammatory changes in response to sephadex beads as observed by H and E staining. However, dexamethasone significantly inhibited the granulomatous changes, and the infiltration of inflammatory cells into the periphery of the lesion, which corroborated with the BALF WBC count. TNF-α and LTB-4 can stimulate the release of the pro-fibrotic cytokine, which can contribute to subepithelial fibrosis in asthma. [24] In the present study, as revealed by the Masson's trichrome staining, sephadex challenge caused a pronounced deposition of subepithelial collagen degradation product throughout the lungs. However, collagen breakdown product deposition was found to be restricted to the basement membrane in the rosiglitazone treated group, and a mild degradation of collagen was observed in the dexamethasone treated animals.

The MMPs and their inhibitors TIMPs also play a key role in both inflammatory and remodeling pathogenesis. MMPs are particularly potent in degrading basement membrane collagen associated with lung injury in inflammatory processes. MMPs are mainly secreted from the activated neutrophils mononuclear cells. Among the MMPs, gelatinases (MMP-2 and MMP-9) are secreted from the inflammatory cells and degrade basement membrane components and counteract airway wall remodeling caused by fibrosis. In the current study, we examined MMP-2, MMP-9 and TIMP-3 expression in lungs to investigate the molecular mechanism of treatment mediated restoration of lungs architecture. It has been reported that corticosteroids inhibit the production of MMPs and increased expression of TIMP-3 in vitro. [25] We also found suppression of MMP-9 associated with an increase in TIMP-3 expression in lungs tissues of dexamethasone treated animals, which correlated well with the increased neutrophil recruitment. These results suggested that neutrophil recruitment to the respiratory tract and an imbalance between MMP-9 and TIMP-3 might play an important role in sephadex-induced fibrosis. Very recently, it has been reported that TIMP-3 knockout mice exhibit higher expression of pro-inflammatory and lower expression of anti-inflammatory genes. [26] Thus, TIMP-3 may play a key role in maintaining the integrity of the extra cellular matrix in the lungs. In the present study, unlike dexamethasone treatment, we observed a difference in restoration of lung architecture with rosiglitazone. Although the treatment inhibited expression of MMP-9 in lungs from mice exposed to sephadex, it failed to increase TIMP-3 expression and decrease hydroxyproline levels in tissues. This clearly indicates that TIMP-3 expression corroborate well with change in lung architecture.


Our result revealed that up-regulation of TIMP-3 was found to have a direct correlation in predicting dexamethasone mediated inhibition of collagen degradation and restoration of alveolar micro-architecture.


1Cotgreave IA, Duddy SK, Kass GE, Thompson D, Moldéus P. Studies on the anti-inflammatory activity of ebselen. Ebselen interferes with granulocyte oxidative burst by dual inhibition of NADPH oxidase and protein kinase C? Biochem Pharmacol 1989;38:649-56.
2Vlahos R, Bozinovski S. Recent advances in pre-clinical mouse models of COPD. Clin Sci (Lond) 2014;126:253-65.
3Parks WC, Shapiro SD. Matrix metalloproteinases in lung biology. Respir Res 2001;2:10-9.
4Corry DB, Kiss A, Song LZ, Song L, Xu J, Lee SH, et al. Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines. FASEB J 2004;18:995-7.
5Pinto ML, Rodrigues P, Coelho A, Gonçalves C, Bairos V. Detection of MMP-9, MMP-1 and TIMP-1 in the lung of developing mouse after prenatal administration of vitamin A. Microsc Microanal 2008;14:111-2.
6Wong S, Belvisi MG, Birrell MA. MMP/TIMP expression profiles in distinct lung disease models: Implications for possible future therapies. Respir Res 2009;10:72.
7Tian H, Cimini M, Fedak PW, Altamentova S, Fazel S, Huang ML, et al. TIMP-3 deficiency accelerates cardiac remodeling after myocardial infarction. J Mol Cell Cardiol 2007;43:733-43.
8Monteleone I, Federici M, Sarra M, Franzè E, Casagrande V, Zorzi F, et al. Tissue inhibitor of metalloproteinase-3 regulates inflammation in human and mouse intestine. Gastroenterology 2012;143:1277-87.e1.
9Reddy GK, Enwemeka CS. A simplified method for the analysis of hydroxyproline in biological tissues. Clin Biochem 1996;29:225-9.
10Mautino G, Henriquet C, Jaffuel D, Bousquet J, Capony F. Tissue inhibitor of metalloproteinase-1 levels in bronchoalveolar lavage fluid from asthmatic subjects. Am J Respir Crit Care Med 1999;160:324-30.
11Lane NE. An update on glucocorticoid-induced osteoporosis. Rheum Dis Clin North Am 2001;27:235-53.
12Standiford TJ, Keshamouni VG, Reddy RC. Peroxisome proliferator-activated receptor-{gamma} as a regulator of lung inflammation and repair. Proc Am Thorac Soc 2005;2:226-31.
13Benayoun L, Letuve S, Druilhe A, Boczkowski J, Dombret MC, Mechighel P, et al. Regulation of peroxisome proliferator-activated receptor gamma expression in human asthmatic airways: Relationship with proliferation, apoptosis, and airway remodeling. Am J Respir Crit Care Med 2001;164:1487-94.
14Honda K, Marquillies P, Capron M, Dombrowicz D. Peroxisome proliferator-activated receptor gamma is expressed in airways and inhibits features of airway remodeling in a mouse asthma model. J Allergy Clin Immunol 2004;113:882-8.
15Hetzel M, Walcher D, Grüb M, Bach H, Hombach V, Marx N. Inhibition of MMP-9 expression by PPARgamma activators in human bronchial epithelial cells. Thorax 2003;58:778-83.
16Corbel M, Lagente V, Théret N, Germain N, Clément B, Boichot E. Comparative effects of betamethasone, cyclosporin and nedocromil sodium in acute pulmonary inflammation and metalloproteinase activities in bronchoalveolar lavage fluid from mice exposed to lipopolysaccharide. Pulm Pharmacol Ther 1999;12:165-71.
17Namovic MT, Walsh RE, Goodfellow C, Harris RR, Carter GW, Bell RL. Pharmacological modulation of eosinophil influx into the lungs of Brown Norway rats. Eur J Pharmacol 1996;315:81-8.
18Ward JE, Tan X. Peroxisome proliferator activated receptor ligands as regulators of airway inflammation and remodelling in chronic lung disease. PPAR Res 2007;2007:14983.
19Torii A, Miyake M, Morishita M, Ito K, Torii S, Sakamoto T. Vitamin A reduces lung granulomatous inflammation with eosinophilic and neutrophilic infiltration in Sephadex-treated rats. Eur J Pharmacol 2004;497:335-42.
20Davis RJ, Murdoch CE, Ali M, Purbrick S, Ravid R, Baxter GS, et al. EP4 prostanoid receptor-mediated vasodilatation of human middle cerebral arteries. Br J Pharmacol 2004;141:580-5.
21Walch L, de Montpreville V, Brink C, Norel X. Prostanoid EP (1)- and TP-receptors involved in the contraction of human pulmonary veins. Br J Pharmacol 2001;134:1671-8.
22Uhm TG, Kim BS, Chung IY. Eosinophil development, regulation of eosinophil-specific genes, and role of eosinophils in the pathogenesis of asthma. Allergy Asthma Immunol Res 2012;4:68-79.
23Hazra S, Batra RK, Tai HH, Sharma S, Cui X, Dubinett SM. Pioglitazone and rosiglitazone decrease prostaglandin E2 in non-small-cell lung cancer cells by up-regulating 15-hydroxyprostaglandin dehydrogenase. Mol Pharmacol 2007;71:1715-20.
24Doherty T, Broide D. Cytokines and growth factors in airway remodeling in asthma. Curr Opin Immunol 2007;19:676-80.
25Leco KJ, Khokha R, Pavloff N, Hawkes SP, Edwards DR. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem 1994;269:9352-60.
26Gill SE, Gharib SA, Bench EM, Sussman SW, Wang RT, Rims C, et al. Tissue inhibitor of metalloproteinases-3 moderates the proinflammatory status of macrophages. Am J Respir Cell Mol Biol 2013;49:768-77.