Pulmonary Complications of Gastric Fluid and Bile Salts Aspiration, an Experimental Study in Rat

Document Type: Original Article


1 Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran

2 1Physiology Research Center, Kerman University of Medical Sciences, Kerman, Iran

3 Kerman Research Center in Modeling for Health (RCMH), Kerman University of Medical Sciences, Kerman, Iran



Gastroesophageal Reflux Disease (GERD) is one of the most common digestive disorders that frequently lead to pulmonary complications due to gastric fluid aspiration. In the present experimental study, chronic aspiration of gastric fluid, its components and bile salts in rat lung was performed to find out the main factor(s) causing pulmonary complications of gastric fluid aspiration.
Materials and Methods:
Forty eight male rats weighted 250-300 g were selected in six groups. After anesthesia and tracheal cannulation, the animals received 0.5 ml/kg normal saline, 0.5 ml/kg of whole gastric fluid, 0.5 ml/kg pepsin (2.5 μg/ml), 0.5 ml/kg hydrochloric acid (pH=1.5) or 0.5 ml/kg bile salts (2.5 μg/ml) by injection into their trachea and lungs. In sham group nothing was injected.
Parenchymal and airways inflammation and fibrosis of bronchi, bronchioles and parenchyma were significantly more in the test groups compared to saline and sham groups (P<0.001); also inflammation in pepsin and bile salts groups (histopathology scores: 2.87±0.35 and 3.0±0.0 for bronchial, 2.87±0.35 and 2.87±0.35 for bronchioles, 2.87±0.35 and 2.87±0.35 for parenchymal inflammation) were more than hydrochloric acid and gastric fluid groups (1.75±0.46 and 2.5±0.53 for bronchial, 2.0±0.0 and 2.0±0.0 for bronchioles, 2.0±0.0 and 2.0±0.0 for parenchymal inflammation) (P<0.05). The same results were found for fibrosis, so that the fibrosis in pepsin and bile salts groups were more than hydrochloric acid and gastric fluid groups (P<0.05).
: The present results suggested that pulmonary complications causing from bile salts and pepsin might be more than gastric juice and hydrochloric acid.


1. Kasper DL, Braunwald E, Fauci AS, Kasper DL, Fauci AS, Longo DL, et al. Diseases of the esophagus in: Harrison's principles of internal medicine, 17th ed. New York: MC Grew-Hill Medical Publishing Division; 2008.

2. Richter JE. Typical and atypical presentations of gastro esophageal reflux disease. The role of esophageal testing in diagnosis and management. Gastroenterol Clin North Am 1996; 25:75-102.

3. Poelmans J, Tack J. Extra-oesophageal manifestations of gastro esophageal reflux. Gut 2005; 54:1492-1499.

4. Tobin RW, Pope CE 2nd, Pellegrini CA, Emond MJ, Sillery J, Raghu G. Increased prevalence of gastroesophageal reflux in patients with Idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 1998; 158:1804-1808.

5. Li B, Hartwig MG, Appel JZ, Bush EL, Balsara KR, Holzknecht ZE, et al. Chronic Aspiration of Gastric fluid Induces the Development of obliterative bronchiolitis in Rat lung Transplants. Am J Transplant 2008; 8:1614-1621.

6. Downing TE, Sporn TA, Bollinger RR, Davis RD, Parker W, Lin SS. Pulmonary histopathology in an experimental model of chronic aspiration is independent of acidity. Exp Biol Med 2008; 233:1202-1212.

7. Appel JZ, Lee SM, Hartwig MG, Li B, Hsieh CC, Cantu E, et al. Characterization of the innate immune response to chronic aspiration in a novel rodent model. Respir Res 2007; 8:87.

8. Kwan M, XU YD, Raghu G, Khalil N, Vancouver BC, Seattle WA. Acid treatment of normal rat lungs releases transforming growth factor –beta 1 (TGF-beta 1) and increases connective tissue synthesis. Am J Respir Crit Care Med 2007; A 967.

9. D'Ovidio F, Mura M, Tsang M, Waddell TK, Hutcheon MA, Singer LG, et al . Bile acid aspiration and the development of bronchiolitis obliterans after lung Transplantation. J Thorac Cardiovasc Surg. 2005; 129:1144-1152.

10. Harding SM. Gastroesophageal reflux: a potential asthma trigger. Immunol Allergy Clin North Am 2005 ; 25:131-148.

11. Carpagnano GE, Resta O, Ventura MT, Amoruso AC, Di Gioia G, Giliberti T, et al. Airway inflammation in subjects with gastro-oesophageal reflux and gastro-oesophageal reflux-related asthma. J Intern Med 2006; 259:323-331.

12. Terada K, Muro S, Ohara T, Kudo M, Ogawa E, Hoshino Y, et al.. Abnormal swallowing reflex and COPD exacerbations. Chest 2010; 137:326-332.

Samareh Fekri M et al Pulmonary Complications of Gastric Fluid Aspiration

Iran J Basic Med Sci, Vol. 16, No. 6, Jun 2013



13. Blondeau K, Mertens V, Vanaudenaerde BA, Verleden GM, Van Raemdonck DE, Sifrim D, et al. Gastro-oesophageal reflux and gastric aspiration in lung transplant patients with or without chronic rejection. Eur Respir J 2008; 31:707-713.

14. Oelberg DG, Downey SA, Flynn MM. Bile salt induced intracellular Ca++ accumulation in type II pneumocytes. Lung 1990; 168:297-308.

15. Hartwig MG, Appel JZ, Li B, Hsieh CC, Yoon YH, Lin SS, et al. Chronic aspiration of gastric fluid accelerates pulmonary allograft dysfunction in a rat model of lung transplantation. J Thoracic Cardiovasc Surg 2006; 131:209-217.

16. Sur S, Wild JS, Choudhury BK, Sur N, Alam R, Klinman DM. Long term prevention of allergic lung inflammation in a mouse model of asthma by CpG Oligodeoxynucleotides. J Immunol. 1999; 162:6284-6293.

17. Kwak YG, Song CH, Yi HK, Hwang PH, Kim JS, Lee KS, et al. Involvement of PTEN in airway hyper responsiveness and inflammation in bronchial asthma. J Clin Invest 2003; 111:1083-1092.

18. Cho KJ, Seo JM, Shin Y, Yoo MH, Park CS, Lee SH, et -al. Blockade of airway inflammation and hyperresponsiveness by inhibition of BLT2, a low-affinity leukotriene B4 receptor. Am J Respir Cell Mol Biol 2010; 42:294-303.

19. Ashcroft T, Simpson JM and Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol 1988 ; 41:467–470.

20. Lee JS, Collard HC, Raghu G, Sweet MP, Hays SR, Campos GM, et al. Dose chronic microaspiration cause idiopathic pulmonary fibrosis? Am J Med 2010; 123:304–311.

21. Hoyoux C, Forget P, Lambrechts L, Geubelle F. Chronic broncho pulmonary disease and gastroesophageal reflux in children. Pediatr Pulmonol 1985; 1:149-153.

22. King BJ, Iyer H, Leidi AA, Carby MR. Gastroesophageal reflux in bronchiolitis obliterans syndrome: a new perspective. J Heart Lung Transplant 2009; 28:870-875.

23. Perng DW, Chang KT, Su KC, Wu YC, Wu MT, Hsu WH,, et al. Exposure of airway epithelium to bile acids associated with gastroesophageal reflux symptoms: a relation to transforming growth factor-beta1 production and fibroblast proliferation.. Chest 2007; 132:1548-1556.

24. DiGiovine B, Lynch JP 3rd, Martinez FJ, Flint A, Whyte RI, Iannettoni MD, et al. Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation. Role of IL- 8. J Immunol 1996;157:4194-4202.

25. Oue K, Mukaisho K, Higo T, Araki Y, Nishikawa M, Hattori T, et al. Histological examination of the relationship between respiratory disorders and repetitive microaspiration using a rat gastro-duodenal contents reflux model. Exp Anim 2011; 60:141-150.