Hypertonic saline and pentoxifylline reduces hemorrhagic shock resuscitation-induced pulmonary inflammation through attenuation of neutrophil degranulation and proinflammatory mediator synthesis.
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 and immunohistochemistry.


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.


CONCLUSIONS
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.
Deree
Jessica
J
Division of Trauma and Surgical Critical Care, Department of Surgery, University of California School of Medicine, San Diego, CA, USA.
Martins
Joilson O
JO
Leedom
Alex
A
Lamon
Brian
B
Putnam
James
J
de Campos
Tercio
T
Hoyt
David B
DB
Wolf
Paul
P
Coimbra
Raul
R
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D015550:Cell Degranulation; D004797:Enzyme-Linked Immunosorbent Assay; D005440:Fluid Therapy / Q000009:adverse effects* / Q000379:methods; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018945:Monocyte Chemoattractant Proteins / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects*; D009504:Neutrophils / Q000502:physiology; D010431:Pentoxifylline / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D012462:Saline Solution, Hypertonic / Q000494:pharmacology / Q000627:therapeutic use*; D012771:Shock, Hemorrhagic / Q000628:therapy*
D018836:Inflammation Mediators; D018945:Monocyte Chemoattractant Proteins; D012462:Saline Solution, Hypertonic; D051547:Heme Oxygenase-1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D010431:Pentoxifylline