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Hypertonic Saline and Pentoxifylline Reduces Hemorrhagic Shock Resuscitation-Induced Pulmonary Inflammation Through Attenuation of Neutrophil Degranulation and Proinflammatory Mediator Synthesis

Deree, Jessica MD; Martins, Joilson O. PharmD; Leedom, Alex BS; Lamon, Brian BS; Putnam, James BS; de Campos, Tercio MD; Hoyt, David B. MD; Wolf, Paul MD; Coimbra, Raul MD, PhD

The Journal of Trauma: Injury, Infection, and Critical Care: January 2007 - Volume 62 - Issue 1 - p 104-111
doi: 10.1097/TA.0b013e31802d96cb
Original Articles
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Background: Ringer’s lactate (RL), the current standard resuscitation fluid, potentiates neutrophil activation and is associated with pulmonary inflammation. Resuscitation with hypertonic saline and pentoxifylline (HSPTX) has been shown to attenuate hemorrhagic shock–induced injury when compared with RL. Because the neutrophil plays a major role in postshock inflammation, we hypothesized that HSPTX reduces pulmonary inflammation after resuscitation in comparison to RL.

Methods: Sprague-Dawley rats underwent controlled shock and were resuscitated with RL (32 mL/kg) or HSPTX (4 mL/kg 7.5% NaCl + pentoxifylline 25 mg/kg). Animals who did not undergo shock or resuscitation served as controls. After 24 hours, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. Cytokine induced neutrophil chemoattractant (CINC) was measured in BALF by enzyme-linked immunosorbent assay. Matrix metalloproteinases (MMP)-2 and -9 were measured by zymography. Hemeoxygenase-1 (HO-1) was assessed by Western blot andimmunohistochemistry.

Results: HSPTX resuscitation led to a 62% decrease in CINC levels compared with RL (p < 0.01). BALF MMP-2 expression was attenuated by 11% with HSPTX (p = 0.09). Lung MMP-2 and MMP-9 expression was reduced by 89% (p < 0.01) and 76%, respectively (p < 0.05). Lung HO-1 expression declined by 34% with HSPTX in comparison to RL (p < 0.01), indicating less oxidative injury. Lung immunohistochemistry localized HO-1 to neutrophils, macrophages, and airway epithelial cells.

Conclusion: Collectively, the attenuation of pulmonary inflammation with HSPTX after shock when compared with RL is associated with downregulation of neutrophil activation, oxidative stress, and proinflammatory mediator production.

From the Division of Trauma and Surgical Critical Care, Department of Surgery, University of California School of Medicine, San Diego, CA.

Submitted for publication March 13, 2006.

Accepted for publication October 31, 2006.

Presented at the 36th Annual Meeting of the Western Trauma Association, February 28–March 3, 2006, Big Sky, Montana.

Address for reprints: Raul Coimbra MD, PhD, FACS, 200 W. Arbor Drive, #8896, San Diego, CA, 92103-8896; email: rcoimbra@ucsd.edu.

© 2007 Lippincott Williams & Wilkins, Inc.