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(Chest. 2003;124:2407-2408.)
© 2003 American College of Chest Physicians

Mice Are Resistant to the Induction of a Pleurodesis

Ioannis Kalomenidis, MD; Kirk Lane, PhD; Timothy S. Blackwell, MD, FCCP; Yubiao Guo, MD and Richard W. Light, MD, FCCP

Athens Medical School Athens, Greece Vanderbilt University Nashville, TN

Correspondence to: Ioannis Kalomenidis, MD, Department of Critical Care and Pulmonary Services, Athens Medical School, "Evangelismos" Hospital, 45-47 Ipsilandou Str, 10675 Athens, Greece; e-mail: jkalomenidis{at}hotmail.com

To the Editor:

Our group has shown that transforming growth factor (TGF)-ß2 produces excellent pleurodesis when administered intrapleurally in rabbits and sheep.1 2 3 It induces pleurodesis faster than talc, and the pleural fluid that is produced after its intrapleural administration is less inflammatory than that produced after the administration of talc or doxycycline. Hence, pleurodesis caused by TGF-ß2 may be effective but less painful and safer when compared to the pleurodesis caused by sclerosing agents currently used in clinical practice.

However, the mechanisms of pleurodesis induced by TGF-ß2 as well as by conventional agents are largely unknown. In order to expand our capabilities of examining the molecular mechanisms of pleurodesis induced by TGF-ß2 or other agents, we attempted to create a mouse model of pleurodesis. A mouse model of pleurodesis would be superior to the rabbit or sheep models for the following reasons: (1) the availability of knockout mice strains would allow one to investigate the mechanism of pleurodesis in more depth, (2) there are many more commercial reagents specific for mice proteins than for sheep or rabbit proteins, and (3) mice are much less expensive.

TGF-ß2 was injected intrapleurally in ICR mice at doses 0.8 to 1,360 µg/kg (Table 1 ). Talc, 4g/kg, and doxycycline, 20 to 100 mg/kg, were also injected. During the first experiments, we combined the "effective" agent with India ink to verify successful intrapleural injection. Since the injection rate was successful in > 95%, we performed the next experiments without ink to eliminate the possibility that the ink reduced the TGF-ß2 activity. Since epidermal growth factor (EGF) is believed to amplify the fibrosing effect of TGF-ß2, we injected some mice with the combination of the two growth factors and with EGF alone. Mice were killed at the 14th day after the injection, and the thorax was examined for pleurodesis. A scale from 1 to 8 was used to evaluate the degree of pleurodesis: 1 = no adhesions, 2 = rare adhesions with no symphysis, 3 = a few scattered adhesions with no symphysis, 4 = many adhesions with no symphysis, 5 = many adhesions with symphysis involving < 5% of the thoracic cavity, 6 = many adhesions with symphysis involving 5 to 25% of the thoracic cavity, 7 = many adhesions with symphysis involving 25 to 50% of the thoracic cavity, and 8 = many adhesions with symphysis involving > 50% of the thoracic cavity.


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  		Table 1. Pleurodesis Score in Different Treatment Groups*

 
TGF-ß2 did not induce pleurodesis, even when administered at doses 130 times higher than the dose that induced intensive pleural fibrosis in rabbits. No more than few scattered pleural adhesions were observed. Furthermore, clinically significant pleurodesis was not observed in any of the mice receiving talc or doxycycline, even when they were administered in doses 10 times higher than those that induce pleurodesis in rabbits. Because different mice strain show different susceptibility for pulmonary fibrosis and C57/Bl-6 mice have been shown to be particularly susceptible to pulmonary fibrosis,4 we injected the TGF-ß2 in eight C57/Bl-6 mice to rule out the possibility that the failure of TGF-ß2 to produce pleurodesis was due to the mouse strain we initially used (ICR mice). As it is shown in Table 1 , TGF-ß2 also failed to induce significant pleurodesis in these mice.

We conclude from this series of experiments that TGF-ß2, doxycycline, and talc do not induce pleurodesis when administered intrapleurally in mice at relatively high doses. The explanation for the refractoriness of the mouse for the induction of a pleurodesis is unknown.

References

  1. Light, RW, Cheng, DS, Lee, YC, et al (2000) A single intrapleural injection of transforming growth factor-ß(2) produces an excellent pleurodesis in rabbits. Am J Respir Crit Care Med 162,98-104[Abstract/Free Full Text]
  2. Lee, YC, Lane, KB, Parker, RE, et al Transforming growth factor ß(2) (TGF ß(2)) produces effective pleurodesis in sheep with no systemic complications. Thorax 2000;55,1058-1062[Abstract/Free Full Text]
  3. Gary Lee, YC, Teixeira, LR, Devin, CJ, et al Transforming growth factor-ß2 induces pleurodesis significantly faster than talc. Am J Respir Crit Care Med 2001;163,640-644[Abstract/Free Full Text]
  4. Warshamana, GS, Pociask, DA, Sime, P, et al Susceptibility to asbestos-induced and transforming growth factor-ß1-induced fibroproliferative lung disease in two strains of mice. Am J Respir Cell Mol Biol 2002;27,705-713[Abstract/Free Full Text]




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