• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jcinvestThe Journal of Clinical InvestigationCurrent IssueArchiveSubscriptionAbout the Journal
J Clin Invest. Mar 1, 1997; 99(5): 944–952.
PMCID: PMC507902

Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model.

Abstract

We examined the effect of ventilation strategy on lung inflammatory mediators in the presence and absence of a preexisting inflammatory stimulus. 55 Sprague-Dawley rats were randomized to either intravenous saline or lipopolysaccharide (LPS). After 50 min of spontaneous respiration, the lungs were excised and randomized to 2 h of ventilation with one of four strategies: (a) control (C), tidal volume (Vt) = 7 cc/kg, positive end expiratory pressure (PEEP) = 3 cm H2O; (b) moderate volume, high PEEP (MVHP), Vt = 15 cc/kg; PEEP = 10 cm H2O; (c) moderate volume, zero PEEP (MVZP), Vt = 15 cc/kg, PEEP = 0; or (d) high volume, zero PEEP (HVZP), Vt = 40 cc/kg, PEEP = 0. Ventilation with zero PEEP (MVZP, HVZP) resulted in significant reductions in lung compliance. Lung lavage levels of TNFalpha, IL-1beta, IL-6, IL-10, MIP-2, and IFNgamma were measured by ELISA. Zero PEEP in combination with high volume ventilation (HVZP) had a synergistic effect on cytokine levels (e.g., 56-fold increase of TNFalpha versus controls). Identical end inspiratory lung distention with PEEP (MVHP) resulted in only a three-fold increase in TNFalpha, whereas MVZP produced a six-fold increase in lavage TNFalpha. Northern blot analysis revealed a similar pattern (C, MVHP < MVZP < HVZP) for induction of c-fos mRNA. These data support the concept that mechanical ventilation can have a significant influence on the inflammatory/anti-inflammatory milieu of the lung, and thus may play a role in initiating or propagating a local, and possibly systemic inflammatory response.

Full Text

The Full Text of this article is available as a PDF (324K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • West JB, Mathieu-Costello O. Stress failure of pulmonary capillaries: role in lung and heart disease. Lancet. 1992 Sep 26;340(8822):762–767. [PubMed]
  • Parker JC, Hernandez LA, Peevy KJ. Mechanisms of ventilator-induced lung injury. Crit Care Med. 1993 Jan;21(1):131–143. [PubMed]
  • Slutsky AS. Consensus conference on mechanical ventilation--January 28-30, 1993 at Northbrook, Illinois, USA. Part I. European Society of Intensive Care Medicine, the ACCP and the SCCM. Intensive Care Med. 1994;20(1):64–79. [PubMed]
  • Montgomery AB, Stager MA, Carrico CJ, Hudson LD. Causes of mortality in patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1985 Sep;132(3):485–489. [PubMed]
  • Meduri GU, Kohler G, Headley S, Tolley E, Stentz F, Postlethwaite A. Inflammatory cytokines in the BAL of patients with ARDS. Persistent elevation over time predicts poor outcome. Chest. 1995 Nov;108(5):1303–1314. [PubMed]
  • Reid PT, Donnelly SC, Haslett C. Inflammatory predictors for the development of the adult respiratory distress syndrome. Thorax. 1995 Oct;50(10):1023–1026. [PMC free article] [PubMed]
  • Donnelly SC, Haslett C. Cellular mechanisms of acute lung injury: implications for future treatment in the adult respiratory distress syndrome. Thorax. 1992 Apr;47(4):260–263. [PMC free article] [PubMed]
  • Kawano T, Mori S, Cybulsky M, Burger R, Ballin A, Cutz E, Bryan AC. Effect of granulocyte depletion in a ventilated surfactant-depleted lung. J Appl Physiol (1985) 1987 Jan;62(1):27–33. [PubMed]
  • Imai Y, Kawano T, Miyasaka K, Takata M, Imai T, Okuyama K. Inflammatory chemical mediators during conventional ventilation and during high frequency oscillatory ventilation. Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 1):1550–1554. [PubMed]
  • Sugiura M, McCulloch PR, Wren S, Dawson RH, Froese AB. Ventilator pattern influences neutrophil influx and activation in atelectasis-prone rabbit lung. J Appl Physiol (1985) 1994 Sep;77(3):1355–1365. [PubMed]
  • Liu M, Xu J, Liu J, Kraw ME, Tanswell AK, Post M. Mechanical strain-enhanced fetal lung cell proliferation is mediated by phospholipase C and D and protein kinase C. Am J Physiol. 1995 May;268(5 Pt 1):L729–L738. [PubMed]
  • Wirtz HR, Dobbs LG. Calcium mobilization and exocytosis after one mechanical stretch of lung epithelial cells. Science. 1990 Nov 30;250(4985):1266–1269. [PubMed]
  • Rannels DE. Role of physical forces in compensatory growth of the lung. Am J Physiol. 1989 Oct;257(4 Pt 1):L179–L189. [PubMed]
  • Vandenburgh HH. Mechanical forces and their second messengers in stimulating cell growth in vitro. Am J Physiol. 1992 Mar;262(3 Pt 2):R350–R355. [PubMed]
  • Sadoshima J, Izumo S. Mechanical stretch rapidly activates multiple signal transduction pathways in cardiac myocytes: potential involvement of an autocrine/paracrine mechanism. EMBO J. 1993 Apr;12(4):1681–1692. [PMC free article] [PubMed]
  • Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. [PubMed]
  • Bezzant TB, Mortensen JD. Risks and hazards of mechanical ventilation: a collective review of published literature. Dis Mon. 1994 Nov;40(11):581–638. [PubMed]
  • Watson PA. Function follows form: generation of intracellular signals by cell deformation. FASEB J. 1991 Apr;5(7):2013–2019. [PubMed]
  • Sachs F. Mechanical transduction by membrane ion channels: a mini review. Mol Cell Biochem. 104(1-2):57–60. [PubMed]
  • Alessandrini F, D'Armini AM, Roberts CS, Reddick RL, Egan TM. When does the lung die? II. Ultrastructural evidence of pulmonary viability after "death". J Heart Lung Transplant. 1994 Sep-Oct;13(5):748–757. [PubMed]
  • Ardekarni RG, Faber LP, Beattie EJ., Jr Pulmonary function after various periods of ischemia in the canine lung. J Thorac Cardiovasc Surg. 1970 May;59(5):607–612. [PubMed]
  • Homatas J, Bryant L, Eiseman B. Time limits of cadaver lung viability. J Thorac Cardiovasc Surg. 1968 Jul;56(1):132–140. [PubMed]
  • Gattinoni L, Presenti A, Torresin A, Baglioni S, Rivolta M, Rossi F, Scarani F, Marcolin R, Cappelletti G. Adult respiratory distress syndrome profiles by computed tomography. J Thorac Imaging. 1986 Jul;1(3):25–30. [PubMed]
  • Gattinoni L, Pesenti A, Baglioni S, Vitale G, Rivolta M, Pelosi P. Inflammatory pulmonary edema and positive end-expiratory pressure: correlations between imaging and physiologic studies. J Thorac Imaging. 1988 Jul;3(3):59–64. [PubMed]
  • Chernoff AE, Granowitz EV, Shapiro L, Vannier E, Lonnemann G, Angel JB, Kennedy JS, Rabson AR, Wolff SM, Dinarello CA. A randomized, controlled trial of IL-10 in humans. Inhibition of inflammatory cytokine production and immune responses. J Immunol. 1995 May 15;154(10):5492–5499. [PubMed]
  • Abraham E, Coulson WF, Schwartz MD, Allbee J. Effects of therapy with soluble tumour necrosis factor receptor fusion protein on pulmonary cytokine expression and lung injury following haemorrhage and resuscitation. Clin Exp Immunol. 1994 Oct;98(1):29–34. [PMC free article] [PubMed]
  • Leff JA, Bodman ME, Cho OJ, Rohrbach S, Reiss OK, Vannice JL, Repine JE. Post-insult treatment with interleukin-1 receptor antagonist decreases oxidative lung injury in rats given intratracheal interleukin-1. Am J Respir Crit Care Med. 1994 Jul;150(1):109–112. [PubMed]
  • Sekido N, Mukaida N, Harada A, Nakanishi I, Watanabe Y, Matsushima K. Prevention of lung reperfusion injury in rabbits by a monoclonal antibody against interleukin-8. Nature. 1993 Oct 14;365(6447):654–657. [PubMed]
  • Kelley J. Cytokines of the lung. Am Rev Respir Dis. 1990 Mar;141(3):765–788. [PubMed]
  • Bendtzen K. Cytokines and natural regulators of cytokines. Immunol Lett. 1994 Dec;43(1-2):111–123. [PubMed]
  • Elias JA, Freundlich B, Kern JA, Rosenbloom J. Cytokine networks in the regulation of inflammation and fibrosis in the lung. Chest. 1990 Jun;97(6):1439–1445. [PubMed]
  • Li XY, Donaldson K, Brown D, MacNee W. The role of tumor necrosis factor in increased airspace epithelial permeability in acute lung inflammation. Am J Respir Cell Mol Biol. 1995 Aug;13(2):185–195. [PubMed]
  • Driscoll KE. Macrophage inflammatory proteins: biology and role in pulmonary inflammation. Exp Lung Res. 1994 Nov-Dec;20(6):473–490. [PubMed]
  • Moore KW, O'Garra A, de Waal Malefyt R, Vieira P, Mosmann TR. Interleukin-10. Annu Rev Immunol. 1993;11:165–190. [PubMed]
  • Muscedere JG, Mullen JB, Gan K, Slutsky AS. Tidal ventilation at low airway pressures can augment lung injury. Am J Respir Crit Care Med. 1994 May;149(5):1327–1334. [PubMed]
  • Bachurski CJ, Pryhuber GS, Glasser SW, Kelly SE, Whitsett JA. Tumor necrosis factor-alpha inhibits surfactant protein C gene transcription. J Biol Chem. 1995 Aug 18;270(33):19402–19407. [PubMed]
  • Arias-Díaz J, Vara E, García C, Gómez M, Balibrea JL. Tumour necrosis factor-alpha inhibits synthesis of surfactant by isolated human type II pneumocytes. Eur J Surg. 1993 Oct;159(10):541–549. [PubMed]
  • Vara E, Arias-Díaz J, García C, Hernández J, Balibrea JL. Both prostaglandin E2 and nitric oxide sequentially mediate the tumor necrosis factor alpha-induced inhibition of surfactant synthesis by human type II pneumocytes. Arch Surg. 1995 Dec;130(12):1279–1286. [PubMed]
  • Seibert AF, Haynes J, Taylor A. Ischemia-reperfusion injury in the isolated rat lung. Role of flow and endogenous leukocytes. Am Rev Respir Dis. 1993 Feb;147(2):270–275. [PubMed]
  • Pison U, Max M, Neuendank A, Weissbach S, Pietschmann S. Host defence capacities of pulmonary surfactant: evidence for 'non-surfactant' functions of the surfactant system. Eur J Clin Invest. 1994 Sep;24(9):586–599. [PubMed]
  • Geertsma MF, Teeuw WL, Nibbering PH, van Furth R. Pulmonary surfactant inhibits activation of human monocytes by recombinant interferon-gamma. Immunology. 1994 Jul;82(3):450–456. [PMC free article] [PubMed]
  • Laskin DL, Soltys RA, Berg RA, Riley DJ. Activation of alveolar macrophages by native and synthetic collagen-like polypeptides. Am J Respir Cell Mol Biol. 1994 Jan;10(1):58–64. [PubMed]
  • Nathan CF. Neutrophil activation on biological surfaces. Massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes. J Clin Invest. 1987 Dec;80(6):1550–1560. [PMC free article] [PubMed]
  • Miles PR, Bowman L, Frazer DG. Properties of lavage material from excised lungs ventilated at different temperatures. Respir Physiol. 1995 Jul;101(1):99–108. [PubMed]
  • Dreyfuss D, Soler P, Saumon G. Mechanical ventilation-induced pulmonary edema. Interaction with previous lung alterations. Am J Respir Crit Care Med. 1995 May;151(5):1568–1575. [PubMed]
  • Xing Z, Jordana M, Kirpalani H, Driscoll KE, Schall TJ, Gauldie J. Cytokine expression by neutrophils and macrophages in vivo: endotoxin induces tumor necrosis factor-alpha, macrophage inflammatory protein-2, interleukin-1 beta, and interleukin-6 but not RANTES or transforming growth factor-beta 1 mRNA expression in acute lung inflammation. Am J Respir Cell Mol Biol. 1994 Feb;10(2):148–153. [PubMed]
  • Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986 May 23;232(4753):977–980. [PubMed]
  • Sadoshima J, Takahashi T, Jahn L, Izumo S. Roles of mechano-sensitive ion channels, cytoskeleton, and contractile activity in stretch-induced immediate-early gene expression and hypertrophy of cardiac myocytes. Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9905–9909. [PMC free article] [PubMed]
  • Komuro I, Kaida T, Shibazaki Y, Kurabayashi M, Katoh Y, Hoh E, Takaku F, Yazaki Y. Stretching cardiac myocytes stimulates protooncogene expression. J Biol Chem. 1990 Mar 5;265(7):3595–3598. [PubMed]
  • Sadoshima J, Jahn L, Takahashi T, Kulik TJ, Izumo S. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells. An in vitro model of load-induced cardiac hypertrophy. J Biol Chem. 1992 May 25;267(15):10551–10560. [PubMed]
  • Klampfer L, Lee TH, Hsu W, Vilcek J, Chen-Kiang S. NF-IL6 and AP-1 cooperatively modulate the activation of the TSG-6 gene by tumor necrosis factor alpha and interleukin-1. Mol Cell Biol. 1994 Oct;14(10):6561–6569. [PMC free article] [PubMed]
  • Angel P, Karin M. The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta. 1991 Dec 10;1072(2-3):129–157. [PubMed]
  • Nathan CF. Secretory products of macrophages. J Clin Invest. 1987 Feb;79(2):319–326. [PMC free article] [PubMed]
  • Tran Van Nhieu J, Misset B, Lebargy F, Carlet J, Bernaudin JF. Expression of tumor necrosis factor-alpha gene in alveolar macrophages from patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1993 Jun;147(6 Pt 1):1585–1589. [PubMed]
  • Crestani B, Cornillet P, Dehoux M, Rolland C, Guenounou M, Aubier M. Alveolar type II epithelial cells produce interleukin-6 in vitro and in vivo. Regulation by alveolar macrophage secretory products. J Clin Invest. 1994 Aug;94(2):731–740. [PMC free article] [PubMed]
  • Nash JR, McLaughlin PJ, Hoyle C, Roberts D. Immunolocalization of tumour necrosis factor alpha in lung tissue from patients dying with adult respiratory distress syndrome. Histopathology. 1991 Nov;19(5):395–402. [PubMed]
  • Dreyfuss D, Soler P, Basset G, Saumon G. High inflation pressure pulmonary edema. Respective effects of high airway pressure, high tidal volume, and positive end-expiratory pressure. Am Rev Respir Dis. 1988 May;137(5):1159–1164. [PubMed]
  • Tutor JD, Mason CM, Dobard E, Beckerman RC, Summer WR, Nelson S. Loss of compartmentalization of alveolar tumor necrosis factor after lung injury. Am J Respir Crit Care Med. 1994 May;149(5):1107–1111. [PubMed]
  • Debs RJ, Fuchs HJ, Philip R, Montgomery AB, Brunette EN, Liggitt D, Patton JS, Shellito JE. Lung-specific delivery of cytokines induces sustained pulmonary and systemic immunomodulation in rats. J Immunol. 1988 May 15;140(10):3482–3488. [PubMed]

Articles from The Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles
  • Substance
    Substance
    PubChem Substance links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...