title: Perivascular fluid cuffs decrease lung compliance by increasing tissue resistance.
abstract: OBJECTIVE
  Lung inflammation causes perivascular fluid cuffs to form around extra-alveolar blood vessels; however, the physiologic consequences of such cuffs remain poorly understood. Herein, we tested the hypothesis that perivascular fluid cuffs, without concomitant alveolar edema, are sufficient to decrease lung compliance.
  
  
  METHODS
  Prospective, randomized, controlled study.
  
  
  METHODS
  Research laboratory.
  
  
  METHODS
  One hundred twenty male CD40 rats.
  
  
  METHODS
  To test this hypothesis, the plant alkaloid thapsigargin was used to activate store-operated calcium entry and increase cytosolic calcium in endothelium. Thapsigargin was infused into a central venous catheter of intact, sedated, and mechanically ventilated rats.
  
  
  METHODS
  Static and dynamic lung mechanics and hemodynamics were measured continuously.
  
  
  RESULTS
  Thapsigargin produced perivascular fluid cuffs along extra-alveolar vessels but did not cause alveolar flooding or blood gas abnormalities. Lung compliance dose-dependently decreased after thapsigargin infusion, attributable to an increase in tissue resistance that was attributed to increased tissue damping and tissue elastance. Airway resistance was not changed. Neither central venous pressure nor left ventricular end diastolic pressure was altered by thapsigargin. Heart rate did not change, although thapsigargin decreased left ventricular systolic function sufficient to reduce cardiac output by 50%. Infusion of the type 4 phosphodiesterase inhibitor, rolipram, prevented thapsigargin from inducing perivascular cuffs and decreasing lung compliance. Rolipram also normalized pressure over time and corrected the deficit in cardiac output.
  
  
  CONCLUSIONS
  Our findings resolve for the first time that perivascular cuff formation negatively impacts mechanical coupling between the bronchovascular bundle and the lung parenchyma, decreasing lung compliance without impacting central venous pressure.
authors.affiliation: Department of Surgery, Center for Lung Biology, University of South Alabama, Mobile, Alabama, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Lowe
authors.forename: Diego F
authors.initials: DF
authors.lastname: Alvarez
authors.forename: Judy A
authors.initials: JA
authors.lastname: King
authors.forename: Troy
authors.initials: T
authors.lastname: Stevens
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015633:Extravascular Lung Water / Q000187:drug effects / Q000502:physiology*; D008170:Lung Compliance / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011654:Pulmonary Edema / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology*; D020889:Rolipram / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
chemical_list: D004791:Enzyme Inhibitors; D010726:Phosphodiesterase Inhibitors; D019284:Thapsigargin; D020889:Rolipram
references.citation: Chest. 1998 Jul;114(1 Suppl):36S-38S
references.pmid: 9676619
references.citation: Circ Res. 1989 Apr;64(4):648-57
references.pmid: 2467760
references.citation: Am J Respir Crit Care Med. 2003 Apr 1;167(7):1027-35
references.pmid: 12663342
references.citation: Am J Respir Cell Mol Biol. 2008 Apr;38(4):386-92
references.pmid: 17962608
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Feb;292(2):L378-80
references.pmid: 17041015
references.citation: Clin Chest Med. 2000 Sep;21(3):435-66
references.pmid: 11019719
references.citation: J Biol Chem. 1991 Sep 15;266(26):17067-71
references.pmid: 1832668
references.citation: Heart Vessels. 1996;11(5):234-41
references.pmid: 9129243
references.citation: J Immunol. 1995 Aug 1;155(3):1515-24
references.pmid: 7636213
references.citation: Am J Pathol. 2007 Mar;170(3):1003-17
references.pmid: 17322384
references.citation: Eur J Pharmacol. 2008 Apr 14;584(1):10-20
references.pmid: 18308301
references.citation: Am J Physiol. 1999 Jan;276(1):L41-50
references.pmid: 9887054
references.citation: Circ Res. 1998 Dec 14-28;83(12):1205-14
references.pmid: 9851937
references.citation: Crit Care Resusc. 2005 Mar;7(1):60-1
references.pmid: 16548822
references.citation: J Am Coll Cardiol. 2008 Mar 18;51(11):1112-9
references.pmid: 18342232
references.citation: Exp Physiol. 1996 Sep;81(5):877-80
references.pmid: 8889484
references.citation: Respir Physiol. 1984 Feb;55(2):223-37
references.pmid: 6729272
references.citation: Pflugers Arch. 1995 Mar;429(5):617-24
references.pmid: 7792139
references.citation: Microvasc Res. 2004 Mar;67(2):139-51
references.pmid: 15020205
references.citation: Microvasc Res. 2004 Jul;68(1):1-12
references.pmid: 15219415
references.citation: Nat Med. 1999 Apr;5(4):392-8
references.pmid: 10202927
references.citation: J Appl Physiol (1985). 2000 Dec;89(6):2241-8
references.pmid: 11090574
references.citation: N Engl J Med. 2000 May 4;342(18):1334-49
references.pmid: 10793167
references.citation: Am J Physiol Cell Physiol. 2006 Jun;290(6):C1572-82
references.pmid: 16421209
references.citation: J Pathol Bacteriol. 1966 Jul;92(1):151-61
references.pmid: 5956252
references.citation: Chest. 2005 Dec;128(6 Suppl):558S-564S
references.pmid: 16373825
references.citation: Circ Res. 2004 Jul 23;95(2):196-203
references.pmid: 15192021
references.citation: IEEE Trans Biomed Eng. 1995 Sep;42(9):860-6
references.pmid: 7558060
references.citation: Ann Thorac Surg. 1999 Jan;67(1):194-9; discussion 199-200
references.pmid: 10086548
references.citation: Am J Physiol. 1997 Jul;273(1 Pt 1):L22-30
references.pmid: 9252536
references.citation: J Appl Physiol. 1959 Mar;14(2):177-86
references.pmid: 13641138
references.citation: J Appl Physiol. 1968 Dec;25(6):729-32
references.pmid: 5727200
references.citation: J Appl Physiol. 1975 Apr;38(4):681-7
references.pmid: 1141099
references.citation: Am J Physiol. 1999 Jun;276(6):L958-60
references.pmid: 10362720
references.citation: J Appl Physiol (1985). 2003 Nov;95(5):1971-8
references.pmid: 12897031
references.citation: Br J Pharmacol. 2003 Sep;140(1):97-106
references.pmid: 12967939
references.citation: Am J Physiol. 1998 May;274(5):L810-9
references.pmid: 9612297
references.citation: Am J Physiol Lung Cell Mol Physiol. 2006 Jul;291(1):L30-7
references.pmid: 16760315
references.citation: Circ Res. 2006 Oct 27;99(9):988-95
references.pmid: 17008604
references.citation: Am J Respir Crit Care Med. 2000 May;161(5):1590-6
references.pmid: 10806160
references.citation: Microcirculation. 2006 Dec;13(8):709-23
references.pmid: 17085429
references.citation: Circ Res. 2005 Apr 29;96(8):856-63
references.pmid: 15790951
references.citation: Am J Physiol Lung Cell Mol Physiol. 2008 Feb;294(2):L266-75
references.pmid: 18083763
references.citation: Annu Rev Biophys Biophys Chem. 1989;18:333-64
references.pmid: 2660829
references.citation: J Appl Physiol (1985). 1997 Sep;83(3):784-91
references.pmid: 9292464
references.citation: Circ Res. 2000 Aug 18;87(4):275-81
references.pmid: 10948060
references.citation: J Surg Res. 2007 Nov;143(1):70-7
references.pmid: 17950075
references.citation: N Engl J Med. 2004 Aug 26;351(9):884-92
references.pmid: 15329426
references.citation: J Appl Physiol. 1972 Jan;32(1):20-4
references.pmid: 5007012
references.citation: J Appl Physiol (1985). 1985 Nov;59(5):1578-84
references.pmid: 4066589
references.citation: Am J Physiol. 1998 Sep;275(3):L574-82
references.pmid: 9728053
references.citation: Eur J Cardiothorac Surg. 2004 May;25(5):833-8
references.pmid: 15082290
references.citation: Am J Physiol Heart Circ Physiol. 2004 Mar;286(3):H1124-32
references.pmid: 14630640
references.citation: Cardiovasc Res. 1999 Aug 1;43(2):382-8
references.pmid: 10536668
references.citation: J Appl Physiol (1985). 1992 Jan;72(1):168-78
references.pmid: 1537711
references.citation: Crit Care Med. 1995 Nov;23(11):1882-9
references.pmid: 7587265
references.citation: Crit Care Clin. 2000 Apr;16(2):289-317
references.pmid: 10768083
references.citation: J Biol Chem. 2007 Nov 30;282(48):34801-8
references.pmid: 17921144