title: Thromboxane A2 mediates increased pulmonary microvascular permeability following limb ischemia.
abstract: Lower torso ischemia and reperfusion lead to respiratory dysfunction characterized by pulmonary hypertension and increased lung microvascular permeability. This is associated with lung leukosequestration and thromboxane (TX) generation. This study tests the role of elevated TX levels following muscle ischemia in mediating remote lung injury. Anesthetized sheep prepared with chronic lung lymph fistulae underwent 2 hours of bilateral hind limb tourniquet ischemia. In untreated controls (n = 7), 1 minute after reperfusion there was a transient increase in plasma immunoreactive (i)-TXB2 levels from 211 to 735 pg/ml (p less than 0.05), and at 30 minutes, lung lymph i-TXB2 levels rose from 400 to 1,005 pg/ml (p less than 0.05). At 1 minute, the mean pulmonary arterial pressure (MPAP) increased from 13 to 38 mm Hg (p less than 0.05) and pulmonary microvascular pressure (Pmv) from 7 to 18 mm Hg (p less than 0.05). Lung lymph flow (QL) rose from 4.3 to 8.3 ml/30 min (p less than 0.05), the lymph/plasma (L/P) protein ratio was unchanged from 0.6, and the lymph protein clearance increased from 2.6 to 4.6 ml/30 min (p less than 0.05). Two hours after reperfusion, neutrophils were observed sequestered in lung capillaries and proteinaceous exudates were found in alveoli in contrast to sham-operated animals (n = 3). To maximize lung vascular surface area and achieve a pressure independent L/P protein ratio a left atrial balloon was inflated during one group of ischemia-reperfusion experiments (n = 5). This resulted in a baseline rise in MPAP to 20 mm Hg (p less than 0.05); a 4.3-fold increase in QL (p less than 0.05), a decrease in the L/P ratio from 0.70 to 0.28 (p less than 0.05) and a protein reflection coefficient (sigma d) of 0.72. During reperfusion the L/P ratio rose to 0.49 (p less than 0.05) and the sigma d decreased to 0.51 (p less than 0.05), documenting an increase in lung microvascular permeability. In contrast to untreated ischemic controls, inhibition of TX synthetase with OKY 046 (n = 6) reduced plasma i-TXB2 levels to 85 pg/ml (p less than 0.05) but also increased i-6-keto-PGF1 alpha levels to 78 pg/ml relative to 15 pg/ml in untreated controls (p less than 0.05). OKY 046 prevented the increase in MPAP, Pmv, QL, and lymph protein clearance (p less than 0.05). Lung histology was normal in distinction to the leukosequestration in untreated ischemic controls.(ABSTRACT TRUNCATED AT 400 WORDS)
authors.affiliation: Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts 02115.
authors.forename: J M
authors.initials: JM
authors.lastname: Klausner
authors.forename: I S
authors.initials: IS
authors.lastname: Paterson
authors.forename: G
authors.initials: G
authors.lastname: Goldman
authors.forename: L
authors.initials: L
authors.lastname: Kobzik
authors.forename: C R
authors.initials: CR
authors.lastname: Valeri
authors.forename: D
authors.initials: D
authors.lastname: Shepro
authors.forename: H B
authors.initials: HB
authors.lastname: Hechtman
mesh_terms: D000818:Animals; D001794:Blood Pressure; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002199:Capillary Permeability; D004338:Drug Combinations; D005231:Fatty Acids, Unsaturated; D005260:Female; D006834:Hydrazines / Q000494:pharmacology; D007052:Ibuprofen / Q000008:administration & dosage / Q000494:pharmacology; D007511:Ischemia / Q000503:physiopathology*; D007866:Leg / Q000098:blood supply*; D008168:Lung / Q000503:physiopathology*; D008689:Methacrylates / Q000008:administration & dosage / Q000494:pharmacology; D008833:Microcirculation; D011651:Pulmonary Artery / Q000502:physiology; D015424:Reperfusion; D012756:Sheep; D013928:Thromboxane A2 / Q000097:blood / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D004338:Drug Combinations; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D008689:Methacrylates; D013928:Thromboxane A2; C045749:SQ 29548; D013930:Thromboxane-A Synthase; C034364:ozagrel; D007052:Ibuprofen