Therapeutic Effect of Adipose Derived Stem Cells versus Atorvastatin on Amiodarone Induced Lung Injury in Male Rat

doi:10.15283/ijsc.2015.8.2.170

. 2015 Nov;8(2):170-80.

doi: 10.15283/ijsc.2015.8.2.170.

Therapeutic Effect of Adipose Derived Stem Cells versus Atorvastatin on Amiodarone Induced Lung Injury in Male Rat

Gihan Ibrahim Aboul-Fotouh¹, Maha Baligh Zickri¹, Hala Gabr Metwally², Ihab Refaat Ibrahim¹, Samaa Samir Kamar¹, Wael Sakr³

Affiliations

¹ Department of Histology, Faculty of Medicine, Cairo University, Cairo, Egypt.
² Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt.
³ Department of Plastic Surgery, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt.

PMID: 26634065
PMCID: PMC4651281
DOI: 10.15283/ijsc.2015.8.2.170

Therapeutic Effect of Adipose Derived Stem Cells versus Atorvastatin on Amiodarone Induced Lung Injury in Male Rat

Gihan Ibrahim Aboul-Fotouh et al. Int J Stem Cells. 2015 Nov.

. 2015 Nov;8(2):170-80.

doi: 10.15283/ijsc.2015.8.2.170.

Authors

Gihan Ibrahim Aboul-Fotouh¹, Maha Baligh Zickri¹, Hala Gabr Metwally², Ihab Refaat Ibrahim¹, Samaa Samir Kamar¹, Wael Sakr³

Affiliations

¹ Department of Histology, Faculty of Medicine, Cairo University, Cairo, Egypt.
² Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt.
³ Department of Plastic Surgery, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt.

PMID: 26634065
PMCID: PMC4651281
DOI: 10.15283/ijsc.2015.8.2.170

Abstract

Background and objectives: Amiodarone (AM), a class 3 antiarrhythmic drug, has been associated with variety of adverse effects, the most serious of which is pulmonary toxicity. Ator (A) is a statin, known for their immunomodulatory and anti-inflammatory activities. Recent studies provide evidence of potential therapeutic effect of statins on lung injury. Adipose derived stem cells (ADSCs) have shown great promise in the repair of various tissues. The present study aimed at investigating and comparing the possible therapeutic effect of A and ADSCs on AM induced lung injury in albino rats.

Methods and results: 34 adult male albino rats were divided into 5 groups: control group (Gp I), A group (Gp II) received 10 mg/kg of A orally 6 days (d)/week (w) for 4 weeks (ws), AM group (Gp III) received 30 mg/kg of AM orally 6 d/w for 4 ws, AM&A group (Gp IV) received AM for 4ws then A for other 4 ws and AM&SCs group (Gp V) received AM for 4 ws then injected with 0.5 ml ADSCs on 2 successive days intravenously (IV). Histological, histochemical, immunohistochemical and morphometric studies were performed. Group III displayed bronchiolitis obliterans, thickened interalveolar septa (IAS) and thickened vascular wall which were proven morphometrically. Increased area% of collagen fibers and apoptotic changes were recorded. All findings regressed on A administration and ADSCs therapy.

Conclusion: Ator proved a definite ameliorating effect on the degenerative, inflammatory, apoptotic and fibrotic changes induced by AM. ADSCs administration denoted more remarkable therapeutic effect compared to A.

Keywords: ADSCs; Amiodarone; Ator; Lung.

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Figures

**Fig. 1**
Lung sections of control rats (H&E) showing (A): a bronchiole (B), a venule (V), an arteriole (ar), alveoli (a), alveolar sacs (A) and IAS (I) (×100), (B): a blood vessel (V) and a bronchiole (B) lined by columnar cells and Clara cells ( ) (×400) (C): alveoli (a) lined mainly by type I pneumocytes ( ). Note few type II pneumocytes ( ) and pulmonary capillaries (c) (×1000). Lung sections in Gp III (H&E) showing (D): obvious thickening of multiple IAS ( ), a distorted bronchiole ( ) and partial thickening of the wall of a venule ( ) (×100), (E): two peribronchial mononuclear aggregates, (MA1) and (MA2). Note obvious thickening of the wall of a vessel ( ) (×100) (F): stratification of the lining epithelium ( ), shed cellular debris ( ) in the lumen of a bronchiole, a congested vessel (c). Note the lining cells with dark nuclei ( ) (×400). (G): thickened IAS harboring multiple fibroblasts (F) surrounded by collagen deposition (*). Note multiple infiltrating cells ( ) (H): multiple type II pneumocytes ( ) and few type I pneumocytes ( ). Note shed cells (*) (×1000).

formula image — **Fig. 1**
Lung sections of control rats (H&E) showing (A): a bronchiole (B), a venule (V), an arteriole (ar), alveoli (a), alveolar sacs (A) and IAS (I) (×100), (B): a blood vessel (V) and a bronchiole (B) lined by columnar cells and Clara cells ( ) (×400) (C): alveoli (a) lined mainly by type I pneumocytes ( ). Note few type II pneumocytes ( ) and pulmonary capillaries (c) (×1000). Lung sections in Gp III (H&E) showing (D): obvious thickening of multiple IAS ( ), a distorted bronchiole ( ) and partial thickening of the wall of a venule ( ) (×100), (E): two peribronchial mononuclear aggregates, (MA1) and (MA2). Note obvious thickening of the wall of a vessel ( ) (×100) (F): stratification of the lining epithelium ( ), shed cellular debris ( ) in the lumen of a bronchiole, a congested vessel (c). Note the lining cells with dark nuclei ( ) (×400). (G): thickened IAS harboring multiple fibroblasts (F) surrounded by collagen deposition (*). Note multiple infiltrating cells ( ) (H): multiple type II pneumocytes ( ) and few type I pneumocytes ( ). Note shed cells (*) (×1000).

**Fig. 2**
Rat lung sections in Gp IV (H&E) showing (A): 2 bronchioles with few shed epithelial cells (*) in their lumens and thickening of some IAS ( ) (×100), (B): focal stratification of the bronchiolar lining epithelium ( ) and few shed cells (*) (×400) (C): numerous type I pneumocytes ( ) and fewer type II pneumocytes ( ) (×1000). In Gp V showing (D): a bronchiole with few shed epithelial cells in the lumen (*) and few thickened IAS ( ). Note a congested vessel (c) (×100), (E): multiple spindle cells (S) in the lumen of a vessel. Note partial thickening ( ) of its wall and few round infiltrating cells in the IAS ( ) (×400) and (F): numerous type I pneumocytes ( ) and fewer type II pneumocytes ( ) (×1000).

**Fig. 3**
(A): Lung sections in Gp I showing fine collagen fibers in the IAS ( ), in the adventitia of a bronchiole ( ) and that of a venule ( ). (B): In Gp III showing dense collagen fibers deposition in thickened IAS ( ), around bronchioles ( ) and around congested blood vessels ( ). (C): In Gp IV showing minimal collagen fibers in the IAS ( ), the adventitia of a bronchiole ( ) and that of a vessel ( ). (D): In Gp V showing minimal collagen fibers in the IAS ( ), the adventitia of a bronchiole ( ) and that of a vessel ( ). (Masson’s trichrome, ×200).

**Fig. 4**
(A): In Gp I showing −ve staining with Pb in a bronchiole (B), alveoli and IAS. In Gp V showing (B): multiple Pb +ve cells surrounding ( ) and inside ( ) a congested blood vessel (c), (C): multiple Pb +ve cells ( ) in thickened IAS (Pb, ×400).

**Fig. 5**
Caspase 3 immunostaining (×400) lung sections (A): in Gp I showing an immunostained +ve cell among the epithelial lining of an alveolus ( ) and another +ve cell in the lining of a bronchiole ( ) (B): In Gp III showing multiple +ve cells in the epithelial lining of alveoli, alveolar sacs ( ) and in thickened IAS ( ) (C): In GP IV showing few +ve cells in the lining epithelium ( ) of 2 alveoli, alveolar sac and in 2 IAS ( ). (D): In GP V showing few +ve cells in the lining epithelium ( ) and adventitia (*) of a bronchiole. Note a +ve cell in the lining epithelium of an alveolus ( ). CD44 immunostaining (×400) lung sections (E): in Gp I showing −ve CD44 immunostaining among the epithelium lining a bronchiole, alveoli and alveolar sacs. (F): In Gp III showing few CD44 +ve spindle cells in obviously thickened IAS ( ) (G): In Gp IV showing multiple +ve spindle cells in thickened IAS ( ). (H): In Gp V showing multiple +ve cuboidal cells (C) and +ve spindle cells (S) among the epithelial lining of alveoli and alveolar sacs.

**Fig. 6**
Histogram comparing (A): the mean values of thickness of IAS in the control and experimental groups, (B): the mean values of thickness of wall of blood vessels in the control and experimental groups, (C): the mean values of area % of collagen fibers in the control and experimental groups, (D): the mean values of area % of caspase 3 +ve cells in the control and experimental groups, (E): the mean values of area % of CD44 +ve cells in the control and experimental groups.

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References

1. Meyer KC. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014;2:1–13. doi: 10.1186/2213-0802-2-4. - DOI - PMC - PubMed
1. Garg J, Agrawal N, Marballi A, Agrawal S, Rawat N, Sule S, Lehrman SG. Amiodarone induced pulmonary toxicity: An unusual response to steroids. Am J Case Rep. 2012;13:62–65. doi: 10.12659/AJCR.882757. - DOI - PMC - PubMed
1. Mankikian J, Favelle O, Guillon A, Guilleminault L, Cormier B, Jonville-Béra AP, Perrotin D, Diot P, Marchand-Adam S. Initial characteristics and outcome of hospitalized patients with amiodarone pulmonary toxicity. Respir Med. 2014;108:638–646. doi: 10.1016/j.rmed.2014.01.014. - DOI - PubMed
1. Minder CM, Blaha MJ, Horne A, Michos ED, Kaul S, Blumenthal RS. Evidence-based use of statins for primary prevention of cardiovascular disease. Am J Med. 2012;125:440–446. doi: 10.1016/j.amjmed.2011.11.013. - DOI - PubMed
1. Malekinejad H, Mehrabi M, Khoramjouy M, Rezaei-Golmisheh A. Antifibrotic effect of atorvastatin on paraquat-induced pulmonary fibrosis: role of PPARγ receptors. Eur J Pharmacol. 2013;720:294–302. doi: 10.1016/j.ejphar.2013.10.013. - DOI - PubMed

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[1] Meyer KC. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014;2:1–13. doi: 10.1186/2213-0802-2-4. - DOI - PMC - PubMed

[2] Meyer KC. Diagnosis and management of interstitial lung disease. Transl Respir Med. 2014;2:1–13. doi: 10.1186/2213-0802-2-4. - DOI - PMC - PubMed

[3] Garg J, Agrawal N, Marballi A, Agrawal S, Rawat N, Sule S, Lehrman SG. Amiodarone induced pulmonary toxicity: An unusual response to steroids. Am J Case Rep. 2012;13:62–65. doi: 10.12659/AJCR.882757. - DOI - PMC - PubMed

[4] Garg J, Agrawal N, Marballi A, Agrawal S, Rawat N, Sule S, Lehrman SG. Amiodarone induced pulmonary toxicity: An unusual response to steroids. Am J Case Rep. 2012;13:62–65. doi: 10.12659/AJCR.882757. - DOI - PMC - PubMed

[5] Mankikian J, Favelle O, Guillon A, Guilleminault L, Cormier B, Jonville-Béra AP, Perrotin D, Diot P, Marchand-Adam S. Initial characteristics and outcome of hospitalized patients with amiodarone pulmonary toxicity. Respir Med. 2014;108:638–646. doi: 10.1016/j.rmed.2014.01.014. - DOI - PubMed

[6] Mankikian J, Favelle O, Guillon A, Guilleminault L, Cormier B, Jonville-Béra AP, Perrotin D, Diot P, Marchand-Adam S. Initial characteristics and outcome of hospitalized patients with amiodarone pulmonary toxicity. Respir Med. 2014;108:638–646. doi: 10.1016/j.rmed.2014.01.014. - DOI - PubMed

[7] Minder CM, Blaha MJ, Horne A, Michos ED, Kaul S, Blumenthal RS. Evidence-based use of statins for primary prevention of cardiovascular disease. Am J Med. 2012;125:440–446. doi: 10.1016/j.amjmed.2011.11.013. - DOI - PubMed

[8] Minder CM, Blaha MJ, Horne A, Michos ED, Kaul S, Blumenthal RS. Evidence-based use of statins for primary prevention of cardiovascular disease. Am J Med. 2012;125:440–446. doi: 10.1016/j.amjmed.2011.11.013. - DOI - PubMed

[9] Malekinejad H, Mehrabi M, Khoramjouy M, Rezaei-Golmisheh A. Antifibrotic effect of atorvastatin on paraquat-induced pulmonary fibrosis: role of PPARγ receptors. Eur J Pharmacol. 2013;720:294–302. doi: 10.1016/j.ejphar.2013.10.013. - DOI - PubMed

[10] Malekinejad H, Mehrabi M, Khoramjouy M, Rezaei-Golmisheh A. Antifibrotic effect of atorvastatin on paraquat-induced pulmonary fibrosis: role of PPARγ receptors. Eur J Pharmacol. 2013;720:294–302. doi: 10.1016/j.ejphar.2013.10.013. - DOI - PubMed

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Therapeutic Effect of Adipose Derived Stem Cells versus Atorvastatin on Amiodarone Induced Lung Injury in Male Rat

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Therapeutic Effect of Adipose Derived Stem Cells versus Atorvastatin on Amiodarone Induced Lung Injury in Male Rat

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