The Role of Cytokines during the Pathogenesis of Ventilator-Associated and Ventilator-Induced Lung Injury

ABSTRACT

Mortality rates from acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) range from 30 to 65%. Although mechanical ventilation (MV) may delay mortality in critically ill patients with ALI/ARDS, it may also cause a lung injury that further promotes and perpetuates ALI/ARDS and multiorgan dysfunction syndrome (MODS). Recent studies have demonstrated that lung protective strategies of MV, as compared with the injurious strategy of conventional MV (CMV) can reduce absolute mortality rates during ALI/ARDS. The protective strategies limit tidal volumes and peak/plateau pressures while maximizing positive end-expiratory pressure. The injury to the lung by CMV is characterized histologically by edema, leukocyte extravasation, and endothelial and epithelial damage. Both human and animal studies suggest that alveolar cell deformation from CMV leads to the release of cytokines/chemokines which orchestrate the extravasation, activation, and recruitment of leukocytes, causing ventilator-associated lung injury (VALI) and ventilator-induced lung injury (VILI). Moreover, VALI/VILI can perpetuate the chronic inflammatory response during ALI/ARDS and MODS. This article explores the role of cytokines/chemokines during the pathogenesis of VALI/VILI.

KEYWORDS

Cytokines - chemokines - leukocytes - ventilator - lung

REFERENCES

• 1 Ware L B, Matthay M A. The acute respiratory distress syndrome.  N Engl J Med. 2000;  342 1334-1349
• 2 Ranieri V M, Suter P M, Tortorella C et al.. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial.  JAMA. 1999;  282 54-61
• 3 Kollef M H, Schuster D P. The acute respiratory distress syndrome.  N Engl J Med. 1995;  332 27-37
• 4 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;  137 1159-1164
• 5 Corbridge T C, Wood L D, Crawford G P, Chudoba M J, Yanos J, Sznajder J I. Adverse effects of large tidal volume and low PEEP in canine acid aspiration.  Am Rev Respir Dis. 1990;  142 311-315
• 6 Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. The Acute Respiratory Distress Syndrome Network.  N Engl J Med. 2000;  342 1301-1308
• 7 West J B, Mathieu-Costello O. Stress failure of pulmonary capillaries: role in lung and heart disease.  Lancet. 1992;  340 762-767
• 8 Hudson L D. Survival data in patients with acute and chronic lung disease requiring mechanical ventilation.  Am Rev Respir Dis. 1989;  140(2 Pt 2) S19-S24
• 9 Gattinoni L, D'Andrea L, Pelosi P, Vitale G, Pesenti A, Fumagalli R. Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome.  JAMA. 1993;  269 2122-2127
• 10 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;  3 59-64
• 11 Gattinoni L, Presenti A, Torresin A et al.. Adult respiratory distress syndrome profiles by computed tomography.  J Thorac Imaging. 1986;  1 25-30
• 12 Bachofen H, Schurch S. Alveolar surface forces and lung architecture.  Comp Biochem Physiol A Mol Integr Physiol. 2001;  129 183-193
• 13 West J B. Invited review: pulmonary capillary stress failure.  J Appl Physiol. 2000;  89 2483-2489 discussion-2497
• 14 Martynowicz M A, Walters B J, Hubmayr R D. Mechanisms of recruitment in oleic acid-injured lungs.  J Appl Physiol. 2001;  90 1744-1753
• 15 Martynowicz M A, Minor T A, Walters B J, Hubmayr R D. Regional expansion of oleic acid-injured lungs.  Am J Respir Crit Care Med. 1999;  160 250-258
• 16 Wyszogrodski I, Kyei-Aboagye K, Taeusch Jr H W, Avery M E. Surfactant inactivation by hyperventilation: conservation by end-expiratory pressure.  J Appl Physiol. 1975;  38 461-466
• 17 Mead J, Takishima T, Leith D. Stress distribution in lungs: a model of pulmonary elasticity.  J Appl Physiol. 1970;  28 596-608
• 18 Webb H H, Tierney D F. Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures: protection by positive end-expiratory pressure.  Am Rev Respir Dis. 1974;  110 556-565
• 19 Dreyfuss D, Saumon G. Ventilator-induced lung injury: lessons from experimental studies.  Am J Respir Crit Care Med. 1998;  157 294-323
• 20 Gordon S. Alternative activation of macrophages.  Nat Rev Immunol. 2003;  3 23-35
• 21 Zingoni A, Sornasse T, Cocks B G, Tanaka Y, Santoni A, Lanier L L. NK cell regulation of T cell-mediated responses.  Mol Immunol. 2005;  42 451-454
• 22 Mosmann T R, Sad S. The expanding universe of T-cell subsets: Th1, Th2 and more.  Immunol Today. 1996;  17 138-146
• 23 Mantovani A, Allavena P, Sica A. Tumour-associated macrophages as a prototypic type II polarised phagocyte population: role in tumour progression.  Eur J Cancer. 2004;  40 1660-1667
• 24 Mantovani A, Schioppa T, Biswas S K, Marchesi F, Allavena P, Sica A. Tumor-associated macrophages and dendritic cells as prototypic type II polarized myeloid populations.  Tumori. 2003;  89 459-468
• 25 Zhai Y, Kupiec-Weglinski J W. What is the role of regulatory T cells in transplantation tolerance?.  Curr Opin Immunol. 1999;  11 497-503
• 26 Mosmann T R, Cherwinski H, Bond M W, Giedlin M A, Coffman R L. Two types of murine helper T cell clone, I: Definition according to profiles of lymphokine activities and secreted proteins.  J Immunol. 1986;  136 2348-2357
• 27 Tremblay L, Valenza F, Ribeiro S P, Li J, Slutsky A S. Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model.  J Clin Invest. 1997;  99 944-952
• 28 Beutler B A. The role of tumor necrosis factor in health and disease.  J Rheumatol. 1999;  26(Suppl 57) 16-21
• 29 Ostensen M E, Thiele D L, Lipsky P E. Tumor necrosis factor-alpha enhances cytolytic activity of human natural killer cells.  J Immunol. 1987;  138 4185-4191
• 30 Frishman J I, Edwards III C K, Sonnenberg M G, Kohno T, Cohen A M, Dinarello C A. Tumor necrosis factor (TNF)-alpha-induced interleukin-8 in human blood cultures discriminates neutralization by the p55 and p75 TNF soluble receptors.  J Infect Dis. 2000;  182 1722-1730
• 31 Moreland L W, McCabe D P, Caldwell J R et al.. Phase I/II trial of recombinant methionyl human tumor necrosis factor binding protein PEGylated dimer in patients with active refractory rheumatoid arthritis.  J Rheumatol. 2000;  27 601-609
• 32 Schottelius A J, Moldawer L L, Dinarello C A, Asadullah K, Sterry W, Edwards III C K. Biology of tumor necrosis factor-alpha: implications for psoriasis.  Exp Dermatol. 2004;  13 193-222
• 33 Piguet P F, Collart M A, Grau G E, Kapanci Y, Vassalli P. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis.  J Exp Med. 1989;  170 655-663
• 34 Suter P M, Suter S, Girardin E, Roux-Lombard P, Grau G E, Dayer J M. High bronchoalveolar levels of tumor necrosis factor and its inhibitors, interleukin-1, interferon, and elastase, in patients with adult respiratory distress syndrome after trauma, shock, or sepsis.  Am Rev Respir Dis. 1992;  145 1016-1022
• 35 Park W Y, Goodman R B, Steinberg K P et al.. Cytokine balance in the lungs of patients with acute respiratory distress syndrome.  Am J Respir Crit Care Med. 2001;  164(10 Pt 1) 1896-1903
• 36 Hyers T M, Tricomi S M, Dettenmeier P A, Fowler A A. Tumor necrosis factor levels in serum and bronchoalveolar lavage fluid of patients with the adult respiratory distress syndrome.  Am Rev Respir Dis. 1991;  144 268-271
• 37 Millar A B, Foley N M, Singer M, Johnson N M, Meager A, Rook G A. Tumour necrosis factor in bronchopulmonary secretions of patients with adult respiratory distress syndrome.  Lancet. 1989;  2 712-714
• 38 Agouridakis P, Kyriakou D, Alexandrakis M G et al.. The predictive role of serum and bronchoalveolar lavage cytokines and adhesion molecules for acute respiratory distress syndrome development and outcome.  Respir Res. 2002;  3 25
• 39 Broccard A F, Hotchkiss J R, Vannay C et al.. Protective effects of hypercapnic acidosis on ventilator-induced lung injury.  Am J Respir Crit Care Med. 2001;  164 802-806
• 40 Broccard A F, Liaudet L, Aubert J D, Schnyder P, Schaller M D. Negative pressure post-tracheal extubation alveolar hemorrhage.  Anesth Analg. 2001;  92 273-275
• 41 Montgomery A B, Stager M A, Carrico C J, Hudson L D. Causes of mortality in patients with the adult respiratory distress syndrome.  Am Rev Respir Dis. 1985;  132 485-489
• 42 von Luettichau I, Nelson P J, Pattison J M et al.. RANTES chemokine expression in diseased and normal human tissues.  Cytokine. 1996;  8 89-98
• 43 Laffey J G, Engelberts D, Kavanagh B P. Buffering hypercapnic acidosis worsens acute lung injury.  Am J Respir Crit Care Med. 2000;  161 141-146
• 44 Laffey J G, Tanaka M, Engelberts D et al.. Therapeutic hypercapnia reduces pulmonary and systemic injury following in vivo lung reperfusion.  Am J Respir Crit Care Med. 2000;  162 2287-2294
• 45 Takata M, Abe J, Tanaka H et al.. Intraalveolar expression of tumor necrosis factor-alpha gene during conventional and high-frequency ventilation.  Am J Respir Crit Care Med. 1997;  156 272-279
• 46 Chu E K, Whitehead T, Slutsky A S. Effects of cyclic opening and closing at low- and high-volume ventilation on bronchoalveolar lavage cytokines.  Crit Care Med. 2004;  32 168-174
• 47 Ricard J D, Dreyfuss D, Saumon G. Production of inflammatory cytokines in ventilator-induced lung injury: a reappraisal.  Am J Respir Crit Care Med. 2001;  163 1176-1180
• 48 de Perrot M, Liu M, Waddell T K, Keshavjee S. Ischemia-reperfusion-induced lung injury.  Am J Respir Crit Care Med. 2003;  167 490-511
• 49 DeMeester S R, Rolfe M W, Kunkel S L et al.. The bimodal expression of tumor necrosis factor-alpha in association with rat lung reimplantation and allograft rejection.  J Immunol. 1993;  150 2494-2505
• 50 Johanson Jr W G, Higuchi J H, Woods D E, Gomez P, Coalson J J. Dissemination of Pseudomonas aeruginosa during lung infection in hamsters: role of oxygen-induced lung injury.  Am Rev Respir Dis. 1985;  132 358-361
• 51 Slutsky A S, Tremblay L N. Multiple system organ failure: is mechanical ventilation a contributing factor?.  Am J Respir Crit Care Med. 1998;  157(6 Pt 1) 1721-1725
• 52 Nahum A, Hoyt J, Schmitz L, Moody J, Shapiro R, Marini J J. Effect of mechanical ventilation strategy on dissemination of intratracheally instilled Escherichia coli in dogs.  Crit Care Med. 1997;  25 1733-1743
• 53 Tschumperlin D J, Oswari J, Margulies A S. Deformation-induced injury of alveolar epithelial cells: effect of frequency, duration, and amplitude.  Am J Respir Crit Care Med. 2000;  162(2 Pt 1) 357-362
• 54 von Bethmann A N, Brasch F, Nusing R et al.. Hyperventilation induces release of cytokines from perfused mouse lung.  Am J Respir Crit Care Med. 1998;  157 263-272
• 55 Murphy D B, Cregg N, Tremblay L et al.. Adverse ventilatory strategy causes pulmonary-to-systemic translocation of endotoxin.  Am J Respir Crit Care Med. 2000;  162 27-33
• 56 Imai Y, Kawano T, Iwamoto S, Nakagawa S, Takata M, Miyasaka K. Intratracheal anti-tumor necrosis factor-alpha antibody attenuates ventilator-induced lung injury in rabbits.  J Appl Physiol. 1999;  87 510-515
• 57 Dinarello C A. Interleukin-1.  Cytokine Growth Factor Rev. 1997;  8 253-265
• 58 Goodman R B, Pugin J, Lee J S, Matthay M A. Cytokine-mediated inflammation in acute lung injury.  Cytokine Growth Factor Rev. 2003;  14 523-535
• 59 Burger D, Chicheportiche R, Giri J G, Dayer J M. The inhibitory activity of human interleukin-1 receptor antagonist is enhanced by type II interleukin-1 soluble receptor and hindered by type I interleukin-1 soluble receptor.  J Clin Invest. 1995;  96 38-41
• 60 Jensen L E, Muzio M, Mantovani A, Whitehead A S. IL-1 signaling cascade in liver cells and the involvement of a soluble form of the IL-1 receptor accessory protein.  J Immunol. 2000;  164 5277-5286
• 61 Dinarello C A. Biologic basis for interleukin-1 in disease.  Blood. 1996;  87 2095-2147
• 62 Arend W P, Welgus H G, Thompson R C, Eisenberg S P. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist.  J Clin Invest. 1990;  85 1694-1697
• 63 Kolb M, Margetts P J, Anthony D C, Pitossi F, Gauldie J. Transient expression of IL-1beta induces acute lung injury and chronic repair leading to pulmonary fibrosis.  J Clin Invest. 2001;  107 1529-1536
• 64 Kadota J, Matsubara Y, Ishimatsu Y et al.. Significance of IL-1beta and IL-1 receptor antagonist (IL-1Ra) in bronchoalveolar lavage fluid (BALF) in patients with diffuse panbronchiolitis (DPB).  Clin Exp Immunol. 1996;  103 461-466
• 65 Smith D R, Kunkel S L, Standiford T J et al.. Increased interleukin-1 receptor antagonist in idiopathic pulmonary fibrosis: a compartmental analysis.  Am J Respir Crit Care Med. 1995;  151 1965-1973
• 66 Rolfe M W, Standiford T J, Kunkel S L et al.. Interleukin-1 receptor antagonist expression in sarcoidosis.  Am Rev Respir Dis. 1993;  148 1378-1384
• 67 Firestein G S, Berger A E, Tracey D E et al.. IL-1 receptor antagonist protein production and gene expression in rheumatoid arthritis and osteoarthritis synovium.  J Immunol. 1992;  149 1054-1062
• 68 Wilkinson R J, Patel P, Llewelyn M et al.. Influence of polymorphism in the genes for the interleukin (IL)-1 receptor antagonist and IL-1beta on tuberculosis.  J Exp Med. 1999;  189 1863-1874
• 69 Belperio J A, DiGiovine B, Keane M P et al.. Interleukin-1 receptor antagonist as a biomarker for bronchiolitis obliterans syndrome in lung transplant recipients.  Transplantation. 2002;  73 591-599
• 70 Dayer J M, de Rochemonteix B, Burrus B, Demczuk S, Dinarello C A. Human recombinant interleukin 1 stimulates collagenase and prostaglandin E2 production by human synovial cells.  J Clin Invest. 1986;  77 645-648
• 71 Wilborn J, Crofford L J, Burdick M D, Kunkel S L, Strieter R M, Peters-Golden M. Cultured lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis have a diminished capacity to synthesize prostaglandin E2 and to express cyclooxygenase-2.  J Clin Invest. 1995;  95 1861-1868
• 72 Naruse K, Shimizu K, Muramatsu M et al.. Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation [see comments].  Arterioscler Thromb. 1994;  14 746-752
• 73 Kallio E A, Koskinen P K, Aavik E, Vaali K, Lemstom K B. Role of nitric oxide in experimental obliterative bronchiolitis (chronic rejection) in the rat.  J Clin Invest. 1997;  100 2984-2994
• 74 Siler T M, Swierkosz J E, Hyers T M, Fowler A A, Webster R O. Immunoreactive interleukin-1 in bronchoalveolar lavage fluid of high-risk patients and patients with the adult respiratory distress syndrome.  Exp Lung Res. 1989;  15 881-894
• 75 Goodman R B, Strieter R M, Martin D P et al.. Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1996;  154(3 Pt 1) 602-611
• 76 Donnelly S C, Strieter R M, Reid P T et al.. The association between mortality rates and decreased concentrations of interleukin-10 and interleukin-1 receptor antagonist in the lung fluids of patients with the adult respiratory distress syndrome.  Ann Intern Med. 1996;  125 191-196
• 77 Goodman R B, Strieter R M, Martin D P et al.. Inflammatory cytokines in patients with persistence of the acute respiratory distress syndrome.  Am J Respir Crit Care Med. 1996;  154(3 Pt 1) 602-611
• 78 Copland I B, Kavanagh B P, Engelberts D, McKerlie C, Belik J, Post M. Early changes in lung gene expression due to high tidal volume.  Am J Respir Crit Care Med. 2003;  168 1051-1059
• 79 Ribeiro S P, Rhee K, Tremblay L, Veldhuizen R, Lewis J F, Slutsky A S. Heat stress attenuates ventilator-induced lung dysfunction in an ex vivo rat lung model.  Am J Respir Crit Care Med. 2001;  163 1451-1456
• 80 Narimanbekov I O, Rozycki H J. Effect of IL-1 blockade on inflammatory manifestations of acute ventilator-induced lung injury in a rabbit model.  Exp Lung Res. 1995;  21 239-254
• 81 Bhatia M, Moochhala S. Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome.  J Pathol. 2004;  202 145-156
• 82 Kishimoto T. Interleukin-6 and its receptor in autoimmunity.  J Autoimmun. 1992;  Apr(5 Suppl A) 123-132
• 83 Rose-John S. Interleukin-6 biology is coordinated by membrane bound and soluble receptors.  Acta Biochim Pol. 2003;  50 603-611
• 84 Aasland D, Oppmann B, Grotzinger J, Rose-John S, Kallen K J. The upper cytokine-binding module and the Ig-like domain of the leukaemia inhibitory factor (LIF) receptor are sufficient for a functional LIF receptor complex.  J Mol Biol. 2002;  315 637-646
• 85 Brunello A G, Weissenberger J, Kappeler A et al.. Astrocytic alterations in interleukin-6/soluble interleukin-6 receptor alpha double-transgenic mice.  Am J Pathol. 2000;  157 1485-1493
• 86 Burger R, Neipel F, Fleckenstein B et al.. Human herpesvirus type 8 interleukin-6 homologue is functionally active on human myeloma cells.  Blood. 1998;  91 1858-1863
• 87 Chow D, He X, Snow A L, Rose-John S, Garcia K C. Structure of an extracellular gp130 cytokine receptor signaling complex.  Science. 2001;  291 2150-2155
• 88 Taga T, Kishimoto T. Gp130 and the interleukin-6 family of cytokines.  Annu Rev Immunol. 1997;  15 797-819
• 89 Taga T, Hibi M, Hirata Y et al.. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130.  Cell. 1989;  58 573-581
• 90 Mullberg J, Althoff K, Jostock T, Rose-John S. The importance of shedding of membrane proteins for cytokine biology.  Eur Cytokine Netw. 2000;  11 27-38
• 91 Peters M, Muller A M, Rose-John S. Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis.  Blood. 1998;  92 3495-3504
• 92 Rose-John S, Heinrich P C. Soluble receptors for cytokines and growth factors: generation and biological function.  Biochem J. 1994;  300(Pt 2) 281-290
• 93 Jones S A, Rose-John S. The role of soluble receptors in cytokine biology: the agonistic properties of the sIL-6R/IL-6 complex.  Biochim Biophys Acta. 2002;  1592 251-263
• 94 Rose-John S. GP130 stimulation and the maintenance of stem cells.  Trends Biotechnol. 2002;  20 417-419
• 95 Leser H G, Gross V, Scheibenbogen C et al.. Elevation of serum interleukin-6 concentration precedes acute-phase response and reflects severity in acute pancreatitis.  Gastroenterology. 1991;  101 782-785
• 96 Remick D G, Bolgos G R, Siddiqui J, Shin J, Nemzek J A. Six at six: interleukin-6 measured 6 h after the initiation of sepsis predicts mortality over 3 days.  Shock. 2002;  17 463-467
• 97 Steinberg J M, Schiller H J, Halter J M et al.. Alveolar instability causes early ventilator-induced lung injury independent of neutrophils.  Am J Respir Crit Care Med. 2004;  169 57-63
• 98 Rich P B, Douillet C D, Hurd H, Boucher R C. Effect of ventilatory rate on airway cytokine levels and lung injury.  J Surg Res. 2003;  113 139-145
• 99 Farrar M A, Schreiber R D. The molecular cell biology of interferon-gamma and its receptor.  Annu Rev Immunol. 1993;  11 571-611
• 100 Thierfelder W E, van Deursen J M, Yamamoto K et al.. Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells.  Nature. 1996;  382 171-174
• 101 Fiorentino D F, Zlotnik A, Mosmann T R, Howard M. A OG: IL-10 inhibits cytokine production by activated macrophages.  J Immunol. 1991;  147 3815-3822
• 102 Segel M J, Izbicki G, Cohen P Y et al.. Role of interferon-gamma in the evolution of murine bleomycin lung fibrosis.  Am J Physiol Lung Cell Mol Physiol. 2003;  285 L1255-L1262
• 103 Wallace W A, Ramage E A, Lamb D, Howie S E. A type 2 (Th2-like) pattern of immune response predominates in the pulmonary interstitium of patients with cryptogenic fibrosing alveolitis (CFA).  Clin Exp Immunol. 1995;  101 436-441
• 104 Varga J, Olsen A, Herhal J, Constantine G, Rosenbloom J, Jimenez S A. Interferon-gamma reverses the stimulation of collagen but not fibronectin gene expression by transforming growth factor-beta in normal human fibroblasts.  Eur J Clin Invest. 1990;  20 487-493
• 105 Stephenson M L, Krane S M, Amento E P, McCroskery P A, Byrne M. Immune interferon inhibits collagen synthesis by rheumatoid synovial cells associated with decreased levels of the procollagen mRNAs.  FEBS Lett. 1985;  180 43-50
• 106 Guyre P M, Morganelli P M, Miller R. Recombinant immune interferon increases immunoglobulin G Fc receptors on cultured human mononuclear phagocytes.  J Clin Invest. 1983;  72 393-397
• 107 Spoelstra F M, Postma D S, Hovenga H, Noordhoek J A, Kauffman H F. Interferon-gamma and interleukin-4 differentially regulate ICAM-1 and VCAM-1 expression on human lung fibroblasts.  Eur Respir J. 1999;  14 759-766
• 108 Skoskiewicz M J, Colvin R B, Schneeberger E E, Russell P S. Widespread and selective induction of major histocompatibility complex-determined antigens in vivo by gamma interferon.  J Exp Med. 1985;  162 1645-1664
• 109 Hobart M, Ramassar V, Goes N, Urmson J, Halloran P F. The induction of class I and II major histocompatibility complex by allogeneic stimulation is dependent on the transcription factor interferon regulatory factor 1 (IRF-1): observations in IRF-1 knockout mice.  Transplantation. 1996;  62 1895-1901
• 110 Hobart M, Ramassar V, Goes N, Urmson J, Halloran P F. IFN regulatory factor-1 plays a central role in the regulation of the expression of class I and II MHC genes in vivo.  J Immunol. 1997;  158 4260-4269
• 111 Hassan A T, Dai Z, Konieczny B T et al.. Regulation of alloantigen-mediated T-cell proliferation by endogenous interferon-gamma: implications for long-term allograft acceptance.  Transplantation. 1999;  68 124-129
• 112 Hidalgo L G, Halloran P F. Role of IFN-gamma in allograft rejection.  Crit Rev Immunol. 2002;  22 317-349
• 113 Giri S N, Hyde D M, Marafino Jr B J. Ameliorating effect of murine interferon gamma on bleomycin-induced lung collagen fibrosis in mice.  Biochem Med Metab Biol. 1986;  36 194-197
• 114 Keane M P, Belperio J A, Burdick M D, Strieter R M. IL-12 attenuates bleomycin-induced pulmonary fibrosis.  Am J Physiol Lung Cell Mol Physiol. 2001;  281 L92-L97
• 115 Raghu G, Brown K K, Bradford W Z et al.. A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.  N Engl J Med. 2004;  350 125-133
• 116 Belperio J A, DiGiovine B, Keane M P et al.. Interleukin-1 receptor antagonist as a biomarker for bronchiolitis obliterans syndrome in lung transplant recipients.  Transplantation. 2002;  73 591-599
• 117 de Waal Malefyt R, Abrams J, Bennett B, Figdor C G, de Vries J E. Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes.  J Exp Med. 1991;  174 1209-1220
• 118 de Waal Malefyt R, Haanen J, Spits H et al.. Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression.  J Exp Med. 1991;  174 915-924
• 119 de Waal Malefyt R, Yssel H, Roncarolo M G, Spits H, de Vries J E. Interleukin-10.  Curr Opin Immunol. 1992;  4 314-320
• 120 de Waal Malefyt R, Yssel H, de Vries J E. Direct effects of IL-10 on subsets of human CD4 + T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation.  J Immunol. 1993;  150 4754-4765
• 121 te Velde A A, de Waal Malefijt R, Huijbens R J, de Vries J E, Figdor C G. IL-10 stimulates monocyte Fc gamma R surface expression and cytotoxic activity: distinct regulation of antibody-dependent cellular cytotoxicity by IFN-gamma, IL-4, and IL-10.  J Immunol. 1992;  149 4048-4052
• 122 Fiorentino D F, Zlotnik A, Vieira P et al.. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells.  J Immunol. 1991;  146 3444-3451
• 123 Bogdan C, Vodovotz Y, Nathan C. Macrophage deactivation by interleukin 10.  J Exp Med. 1991;  174 1549-1555
• 124 Ralph P, Nakoinz I, Sampson-Johannes A et al.. IL-10, T lymphocyte inhibitor of human blood cell production of IL-1 and tumor necrosis factor.  J Immunol. 1992;  148 808-814
• 125 Hsu D H, de Waal Malefyt R, Fiorentino D F et al.. Expression of interleukin-10 activity by Epstein-Barr virus protein BCRF1.  Science. 1990;  250 830-832
• 126 Hsu D H, Moore K W, Spits H. Differential effects of IL-4 and IL-10 on IL-2-induced IFN-gamma synthesis and lymphokine-activated killer activity.  Int Immunol. 1992;  4 563-569
• 127 Chen W F, Zlotnik A. IL-10: a novel cytotoxic T cell differentiation factor.  J Immunol. 1991;  147 528-534
• 128 MacNeil I A, Suda T, Moore K W, Mosmann T R, Zlotnik A. IL-10, a novel growth cofactor for mature and immature T cells.  J Immunol. 1990;  145 4167-4173
• 129 Hu S, Chao C C, Ehrlich L C et al.. Inhibition of microglial cell RANTES production by IL-10 and TGF-beta.  J Leukoc Biol. 1999;  65 815-821
• 130 Bejarano M T, de Waal Malefyt R, Abrams J S et al.. Interleukin 10 inhibits allogeneic proliferative and cytotoxic T cell responses generated in primary mixed lymphocyte cultures.  Int Immunol. 1992;  4 1389-1397
• 131 Inoue G. Effect of interleukin-10 (IL-10) on experimental LPS-induced acute lung injury.  J Infect Chemother. 2000;  6 51-60
• 132 Kusske A M, Rongione A J, Ashley S W, McFadden D W, Reber H A. Interleukin-10 prevents death in lethal necrotizing pancreatitis in mice.  Surgery. 1996;  120 284-288 discussion-289
• 133 Howard M, Muchamuel T, Andrade S, Menon S. Interleukin 10 protects mice from lethal endotoxemia.  J Exp Med. 1993;  177 1205-1208
• 134 Penttinen R P, Kobayashi S, Bornstein P. Transforming growth factor beta increases mRNA for matrix proteins both in the presence and in the absence of changes in mRNA stability.  Proc Natl Acad Sci USA. 1988;  85 1105-1108
• 135 Roberts A B, Sporn M B, Assoian R K et al.. Transforming growth factor type beta: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro.  Proc Natl Acad Sci USA. 1986;  83 4167-4171
• 136 Shull M M, Ormsby I, Kier A B et al.. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.  Nature. 1992;  359 693-699
• 137 Harguindey S. Combined strategy of cancerous cells: fat and protein metabolism: conclusions (3rd of 3 parts).  Med Interna. 1994;  11 351-358
• 138 Pittet J F, Griffiths M J, Geiser T et al.. TGF-beta is a critical mediator of acute lung injury.  J Clin Invest. 2001;  107 1537-1544
• 139 Sime P J, Xing Z, Graham F L, Csaky K G, Gauldie J. Adenovector-mediated gene transfer of active transforming growth factor-beta 1 induces prolonged severe fibrosis in rat lung.  J Clin Invest. 1997;  100 768-776
• 140 Imanaka H, Shimaoka M, Matsuura N, Nishimura M, Ohta N, Kiyono H. Ventilator-induced lung injury is associated with neutrophil infiltration, macrophage activation, and TGF-beta 1 mRNA upregulation in rat lungs.  Anesth Analg. 2001;  92 428-436
• 141 Yamamoto H, Teramoto H, Uetani K, Igawa K, Shimizu E. Cyclic stretch upregulates interleukin-8 and transforming growth factor-beta1 production through a protein kinase C-dependent pathway in alveolar epithelial cells.  Respirology. 2002;  7 103-109
• 142 Rollins B J. Chemokines.  Blood. 1997;  90 909-928
• 143 Luster A D. Review articles: mechanisms of disease: chemokines-chemotactic cytokines that mediate inflammation.  N Engl J Med. 1998;  338 436-445
• 144 Strieter R M, Kunkel S L. Chemokines and the lung. In: Crystal R, West J, Weibel E, et al Lung: Scientific Foundations. 2nd ed. NY: Raven; 1997: 155-186
• 145 Bleul C C, Fuhlbrigge R C, Casasnovas J M, Aiuti A, Springer T A. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). [see comments].  J Exp Med. 1996;  184 1101-1109
• 146 Loetscher M, Gerber B, Loetscher P et al.. Chemokine receptor specific for IP10 and MIG: structure, function, and expression in activated T-lymphocytes [see comments].  J Exp Med. 1996;  184 963-969
• 147 Keane M P, Belperio J A, Arenberg D A et al.. IFN-gamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis.  J Immunol. 1999;  162(9) 5511-5518
• 148 Keane M P, Belperio J A, Moore T A et al.. Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis.  J Immunol. 1999;  162 5511-5518
• 149 Moore B B, Arenberg D A, Addison C L, Keane M P, Strieter R M. Tumor angiogenesis is regulated by CXC chemokines.  J Lab Clin Med. 1998;  132 97-103
• 150 Baggiolini M, Dewald B, Moser B. Human chemokines: an update.  Annu Rev Immunol. 1997;  15 675-705
• 151 Robinson L A, Nataraj C, Thomas D W et al.. A role for fractalkine and its receptor (CX3CR1) in cardiac allograft rejection.  J Immunol. 2000;  165 6067-6072
• 152 Fong A M, Robinson L A, Steeber D A et al.. Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow.  J Exp Med. 1998;  188 1413-1419
• 153 Pan Y, Lloyd C, Zhou H et al.. Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. [published erratum appears in Nature 1997 Sep 4;389:100].  Nature. 1997;  387 611-617
• 154 Bazan J F, Bacon K B, Hardiman G et al.. A new class of membrane-bound chemokine with a CX3C motif.  Nature. 1997;  385 640-644
• 155 Zlotnik A, Yoshie O. Chemokines: a new classification system and their role in immunity.  Immunity. 2000;  12 121-127
• 156 Murphy P M, Baggiolini M, Charo I F et al.. International union of pharmacology, XXII: Nomenclature for chemokine receptors.  Pharmacol Rev. 2000;  52 145-176
• 157 Segerer S, Nelson P J, Schlondorff D. Chemokines, chemokine receptors, and renal disease: from basic science to pathophysiologic and therapeutic studies.  J Am Soc Nephrol. 2000;  11 152-176
• 158 Ahuja S K, Murphy P M. The CXC chemokines growth-regulated oncogene (GRO) alpha, GRObeta, GROgamma, neutrophil-activating peptide-2, and epithelial cell-derived neutrophil-activating peptide-78 are potent agonists for the type B, but not the type A, human interleukin-8 receptor.  J Biol Chem. 1996;  271 20545-20550
• 159 Bowman E P, Campbell J J, Druey K M, Scheschonka A, Kehrl J H, Butcher E C. Regulation of chemotactic and proadhesive responses to chemoattractant receptors by RGS (regulator of G-protein signaling) family members.  J Biol Chem. 1998;  273 28040-28048
• 160 Strieter R M, Polverini P J, Kunkel S L et al.. The functional role of the ELR motif in CXC chemokine-mediated angiogenesis.  J Biol Chem. 1995;  270 27348-27357
• 161 Strieter R M, Belperio J A, Phillips R J, Keane M P. Chemokines: angiogenesis and metastases in lung cancer.  Novartis Found Symp. 2004;  256 173-184 discussion 184-188 259-269
• 162 Strieter R M, Belperio J A, Keane M P. CXC chemokines in vascular remodeling related to pulmonary fibrosis.  Am J Respir Cell Mol Biol. 2003;  29(Suppl 3) S67-S69
• 163 Strieter R M, Belperio J A, Keane M P. CXC chemokines in angiogenesis related to pulmonary fibrosis.  Chest. 2002;  122(Suppl 6) 298S-301S
• 164 Strieter R M, Polverini P J, Arenberg D A et al.. Role of C-X-C chemokines as regulators of angiogenesis in lung cancer.  J Leukoc Biol. 1995;  57 752-762
• 165 Murphy P M, Ahuja S K, Combadiere C, Gao J-L. Chemokiine receptors. In: Koch AE, Strieter RM Chemokines in Disease. Austin, TX RG Landes; 1996: 55-80
• 166 Repine J E, Beehler C J. Neutrophils and adult respiratory distress syndrome: two interlocking perspectives in 1991.  Am Rev Respir Dis. 1991;  144 251-252
• 167 Lee W L, Downey G P. Neutrophil activation and acute lung injury.  Curr Opin Crit Care. 2001;  7 1-7
• 168 Folkesson H G, Matthay M A, Hebert C A, Broaddus V C. Acid aspiration-induced lung injury in rabbits is mediated by interleukin-8-dependent mechanisms.  J Clin Invest. 1995;  96 107-116
• 169 Keane M P, Donnelly S C, Belperio J A et al.. Imbalance in the expression of CXC chemokines correlates with bronchoalveolar lavage fluid angiogenic activity and procollagen levels in acute respiratory distress syndrome.  J Immunol. 2002;  169 6515-6521
• 170 Aikawa A, McLaughlin P J, McDicken I W et al.. TNF staining of graft biopsies in renal transplantation.  Transplantation. 1993;  56 231-233
• 171 Goodman R B, Strieter R M, Frevert C W et al.. Quantitative comparison of C-X-C chemokines produced by endotoxin-stimulated human alveolar macrophages.  Am J Physiol. 1998;  275(1 Pt 1) L87-L95
• 172 Proost P, De Wolf-Peeters C, Conings R, Opdenakker G, Billiau A, Van Damme J. Identification of a novel granulocyte chemotactic protein (GCP-2) from human tumor cells: in vitro and in vivo comparison with natural forms of GRO, IP-10, and IL-8.  J Immunol. 1993;  150 1000-1010
• 173 Villard J, Dayer-Pastore F, Hamacher J, Aubert J D, Schlegel-Haueter S, Nicod L P. GRO alpha and interleukin-8 in Pneumocystis carinii or bacterial pneumonia and adult respiratory distress syndrome.  Am J Respir Crit Care Med. 1995;  152(5 Pt 1) 1549-1554
• 174 Miller E J, Cohen A B, Nagao S et al.. Elevated levels of NAP-1/interleukin-8 are present in the airspaces of patients with the adult respiratory distress syndrome and are associated with increased mortality.  Am Rev Respir Dis. 1992;  146 427-432
• 175 Jorens P G, Van Damme J, De Backer W et al.. Interleukin 8 (IL-8) in the bronchoalveolar lavage fluid from patients with the adult respiratory distress syndrome (ARDS) and patients at risk for ARDS.  Cytokine. 1992;  4 592-597
• 176 Donnelly S C, Strieter R M, Kunkel S L et al.. Interleukin-8 and development of adult respiratory distress syndrome in at-risk patient groups.  Lancet. 1993;  341 643-647
• 177 Kurdowska A, Noble J M, Steinberg K P, Ruzinski J T, Hudson L D, Martin T R. Anti-interleukin 8 autoantibody: interleukin 8 complexes in the acute respiratory distress syndrome: relationship between the complexes and clinical disease activity.  Am J Respir Crit Care Med. 2001;  163 463-468
• 178 Welbourn C R, Goldman G, Paterson I S, Valeri C R, Shepro D, Hechtman H B. Pathophysiology of ischaemia reperfusion injury: central role of the neutrophil.  Br J Surg. 1991;  78 651-655
• 179 Yokoi K, Mukaida N, Harada A, Watanabe Y, Matsushima K. Prevention of endotoxemia-induced acute respiratory distress syndrome-like lung injury in rabbits by a monoclonal antibody to IL-8.  Lab Invest. 1997;  76 375-384
• 180 Sue R D, Belperio J A, Burdick M D et al.. CXCR2 is critical to hyperoxia-induced lung injury.  J Immunol. 2004;  172 3860-3868
• 181 Belperio J A, Keane M P, Burdick M D et al.. Critical role for CXCR2 and CXCR2 ligands during the pathogenesis of ventilator-induced lung injury.  J Clin Invest. 2002;  110 1703-1716
• 182 Kotani M, Kotani T, Ishizaka A et al.. Neutrophil depletion attenuates interleukin-8 production in mild-overstretch ventilated normal rabbit lung.  Crit Care Med. 2004;  32 514-519
• 183 Pugin J, Dunn I, Jolliet P et al.. Activation of human macrophages by mechanical ventilation in vitro.  Am J Physiol. 1998;  275(6 Pt 1) L1040-L1050
• 184 Vlahakis N E, Schroeder M A, Limper A H, Hubmayr R D. Stretch induces cytokine release by alveolar epithelial cells in vitro.  Am J Physiol. 1999;  277(1 Pt 1) L167-L173
• 185 Mourgeon E, Isowa N, Keshavjee S, Zhang X, Slutsky A S, Liu M. Mechanical stretch stimulates macrophage inflammatory protein-2 secretion from fetal rat lung cells.  Am J Physiol Lung Cell Mol Physiol. 2000;  279(4) L699-L706
• 186 Gerard C, Frossard J L, Bhatia M et al.. Targeted disruption of the beta-chemokine receptor CCR1 protects against pancreatitis-associated lung injury.  J Clin Invest. 1997;  100 2022-2027
• 187 Tokuda A, Itakura M, Onai N, Kimura H, Kuriyama T, Matsushima K. Pivotal role of CCR1-positive leukocytes in bleomycin-induced lung fibrosis in mice.  J Immunol. 2000;  164 2745-2751
• 188 Gharaee-Kermani M, McCullumsmith R E, Charo I F, Kunkel S L, Phan S H. CC-chemokine receptor 2 required for bleomycin-induced pulmonary fibrosis.  Cytokine. 2003;  24 266-276
• 189 Moore B B, Paine III R, Christensen P J et al.. Protection from pulmonary fibrosis in the absence of CCR2 signaling.  J Immunol. 2001;  167 4368-4377
• 190 Belperio J A, Keane M P, Burdick M D et al.. Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome.  J Clin Invest. 2001;  108 547-556
• 191 Belperio J A, Dy M, Murray L et al.. The role of the Th2 CC chemokine ligand CCL17 in pulmonary fibrosis.  J Immunol. 2004;  173 4692-4698
• 192 Naik A S, Kallapur S G, Bachurski C J et al.. Effects of ventilation with different positive end-expiratory pressures on cytokine expression in the preterm lamb lung.  Am J Respir Crit Care Med. 2001;  164 494-498
• 193 Belperio J A, Burdick M D, Keane M P et al.. The role of the CC chemokine, RANTES, in acute lung allograft rejection.  J Immunol. 2000;  165 461-472
• 194 Suga M, Maclean A A, Keshavjee S, Fischer S, Moreira J M, Liu M. RANTES plays an important role in the evolution of allograft transplant-induced fibrous airway obliteration.  Am J Respir Crit Care Med. 2000;  162 1940-1948
• 195 Boehler A, Bai X H, Liu M et al.. Upregulation of T-helper 1 cytokines and chemokine expression in post-transplant airway obliteration.  Am J Respir Crit Care Med. 1999;  159 1910-1917
• 196 Monti G, Magnan A, Fattal M et al.. Intrapulmonary production of RANTES during rejection and CMV pneumonitis after lung transplantation.  Transplantation. 1996;  61 1757-1762
• 197 Panoskaltsis-Mortari A, Strieter R M, Hermanson J R et al.. Induction of monocyte- and T-cell-attracting chemokines in the lung during the generation of idiopathic pneumonia syndrome following allogeneic murine bone marrow transplantation.  Blood. 2000;  96 834-839
• 198 Sekine Y, Yasufuku K, Heidler K M et al.. Monocyte chemoattractant protein-1 and RANTES are chemotactic for graft infiltrating lymphocytes during acute lung allograft rejection.  Am J Respir Cell Mol Biol. 2000;  23 719-726
• 199 Altemeier W A, Matute-Bello G, Frevert C W et al.. Mechanical ventilation with moderate tidal volumes synergistically increases lung cytokine response to systemic endotoxin.  Am J Physiol Lung Cell Mol Physiol. 2004;  287 L533-L542