Experimental pulmonary embolism: effects of the thrombus and attenuation of pulmonary artery injury by low-molecular-weight heparin.
BACKGROUND
Pulmonary embolism (PE) is a life-threatening condition that is associated with the long-term sequelae of chronic pulmonary hypertension. Prior experimental work has suggested that post-PE inflammation is accompanied by pulmonary artery intimal hyperplasia. This study evaluated the effect of the thrombus and tested the hypothesis that thrombolytic, antiplatelet, and anticoagulant agents would decrease pulmonary injury.


METHODS
Male Sprague-Dawley rats (n = 267) underwent laparotomy and temporary clip occlusion of the infrarenal inferior vena cava for the formation of endogenous thrombus or placement of an inert silicone "thrombus." Two days later, repeat laparotomy was performed, the clip removed, and the thrombus or silicone plug was embolized to the lungs. The endogenous thrombus group received normal saline, low-molecular-weight heparin (LMWH), tissue plasminogen activator (tPA), or a gIIB/IIIA antagonist (abciximab). Lung tissue was harvested at various times over 21 days and assayed for total collagen, monocyte chemoattractant protein-1 (MCP-1), interleukin-13 (IL-13), and transforming growth factor-beta (TGF-beta). Fixed sections were stained with trichrome for intimal hyperplasia determination and ED-1 monocytes and alpha-actin-positive staining.


RESULTS
The overall survival for rats undergoing PE was 90%, was not affected by treatment, and 84% of all PE localized to the right pulmonary artery. The PE significantly reduced Pa(O2) in all groups. Compared with controls, the silicone emboli group had an increased level of IL-13 on day 1, an increased level of MCP-1 on day 4, and an increase in the levels of all inflammatory mediators on day 14 (P < .05). Accompanying these differences were greater pulmonary artery intimal hyperplasia at days 4 and 21 in the silicone group compared with controls (P < .05). LMWH treatment in the thrombus of PE rats significantly decreased IL-13 levels at all time points, whereas treatment with abciximab or tPA significantly increased IL-13 levels compared with controls. TGF-beta levels were significantly increased by LMWH at day 4 and 14, and abciximab was associated with lower TGF-beta at day 14. Only LMWH was associated with less pulmonary artery intimal hyperplasia at day 14 compared with controls and the other treatment groups.


CONCLUSIONS
Persistent pulmonary artery distention by an inert material is sufficient to invoke significant inflammation and intimal hyperplasia independent of the thrombus itself. Compared with nontreated PE, LMWH is the only therapy associated with a significant reduction in late intimal hyperplasia and, with the exception of TGF-beta, lower profibrotic growth-factor production.
Rectenwald
John E
JE
Department of Surgery, Jobst Vascular Research Laboratory, Section of Vascular Surgery, University of Michigan, Ann Arbor, USA. jrectenw@umich.edu
Deatrick
K Barry
KB
Sukheepod
Pasu
P
Lynch
Erin M
EM
Moore
Andrea J
AJ
Moaveni
Daria M
DM
Dewyer
Nicholas A
NA
Deywer
Nicholas A
NA
Luke
Catherine E
CE
Upchurch
Gilbert R
GR
Wakefield
Thomas W
TW
Kunkel
Steven L
SL
Henke
Peter K
PK
D000792:Angiography; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage*; D001707:Biopsy, Needle; D018925:Chemokines / Q000032:analysis / Q000378:metabolism; D016207:Cytokines / Q000032:analysis / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D007150:Immunohistochemistry; D008297:Male; D011336:Probability; D011651:Pulmonary Artery / Q000473:pathology*; D011655:Pulmonary Embolism / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D015996:Survival Rate
D000925:Anticoagulants; D018925:Chemokines; D016207:Cytokines; D006495:Heparin, Low-Molecular-Weight