Neutrophils are an important component of innate immunity in the lungs. During bacterial pneumonia, neutrophils are recruited from the capillaries of the pulmonary circulation in the gas-exchanging regions of the lungs. This process requires the coordinated activation of many cells within the lungs, including neutrophils and capillary endothelial cells. Cellular activation during innate immune responses is mediated in part by tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-1-initiated signaling through their receptors, activation of nuclear factor kappa B (NF-κB) and downstream gene transcription, endothelial cell signaling initiated by neutrophil adherence to intercellular adhesion molecule (ICAM)-1, and binding of leukocyte adhesion molecules to cellular and matrix ligands. These events are essential to effective host defense during pneumonia.
KEYWORDS
Neutrophils - pneumonia - cytokines - adhesion molecules - host defense
REFERENCES
1
Medzhitov R.
Toll-like receptors and innate immunity.
Nat Rev Immunol.
2001;
1
135-145
2
Ledebur H C, Parks T P.
Transcriptional regulation of the intercellular adhesion molecule-1 gene by inflammatory cytokines in human endothelial cells: essential roles of a variant NF-kappa B site and p65 homodimers.
J Biol Chem.
1995;
270
933-943
3
Wickremasinghe M I, Thomas L H, Friedland J S.
Pulmonary epithelial cells are a source of IL-8 in the response to Mycobacterium tuberculosis: essential role of IL-1 from infected monocytes in a NF-kappa B-dependent network.
J Immunol.
1999;
163
3936-3947
4
Black R A, Rauch C T, Kozlosky C J et al..
A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells.
Nature.
1997;
385
729-733
5
Baud V, Karin M.
Signal transduction by tumor necrosis factor and its relatives.
Trends Cell Biol.
2001;
11
372-377
6
Grell M, Douni E, Wajant H et al..
The transmembrane form of tumor necrosis factor is the prime activating ligand of the 80 kDa tumor necrosis factor receptor.
Cell.
1995;
83
793-802
7
Mukhopadhyay A, Suttles J, Stout R D, Aggarwal B B.
Genetic deletion of the tumor necrosis factor receptor p60 or p80 abrogates ligand-mediated activation of nuclear factor-kappa B and of mitogen-activated protein kinases in macrophages.
J Biol Chem.
2001;
276
31906-31912
8
Dinarello C A.
Interleukin-1.
Cytokine Growth Factor Rev.
1997;
8
253-265
9
Sims J E.
IL-1 and IL-18 receptors, and their extended family.
Curr Opin Immunol.
2002;
14
117-122
10
Nelson S, Bagby G J, Bainton B G et al..
Compartmentalization of intraalveolar and systemic lipopolysaccharide-induced tumor necrosis factor and the pulmonary inflammatory response.
J Infect Dis.
1989;
159
189-194
11
Laichalk L L, Kunkel S L, Strieter R M et al..
Tumor necrosis factor mediates lung antibacterial host defenses in murine Klebsiella pneumonia.
Infect Immun.
1996;
64
5211-5218
12
Fox-Dewhurst R, Alberts M K, Kajikawa O et al..
Pulmonary and systemic inflammatory responses in rabbits with gram-negative pneumonia.
Am J Respir Crit Care Med.
1997;
155
2030-2040
13
Greene C, Lowe G, Taggart C et al..
Tumor necrosis factor-alpha-converting enzyme: its role in community-acquired pneumonia.
J Infect Dis.
2002;
186
1790-1796
14
Bauer T T, Monton C, Torres A et al..
Comparison of systemic cytokine levels in patients with acute respiratory distress syndrome, severe pneumonia, and controls.
Thorax.
2000;
55
46-52
15
Monton C, Torres A, El-Ebiary M et al..
Cytokine expression in severe pneumonia: a bronchoalveolar lavage study.
Crit Care Med.
1999;
27
1745-1753
16
Ulich T R, Watson L R, Yin S M et al..
The intratracheal administration of endotoxin and cytokines, I: Characterization of LPS-induced IL-1 and TNF mRNA expression and the LPS-, IL-1-, and TNF-induced inflammatory infiltrate.
Am J Pathol.
1991;
138
1485-1496
17
Blackwell T S, Lancaster L H, Blackwell T R et al..
Differential NF-κB activation after intratracheal endotoxin.
Am J Pathol.
1991;
138
1485-1496
18
Mizgerd J P, Peschon J J, Doerschuk C M.
Roles of tumor necrosis factor signaling during murine Escherichia coli pneumonia in mice.
Am J Respir Cell Mol Biol.
2000;
22
85-91
19
Mizgerd J P, Spieker M R, Doerschuk C M.
Early response cytokines and innate immunity: essential roles for TNFR1 and IL1R1 during Escherichia coli pneumonia in mice.
J Immunol.
2001;
166
4042-4048
20
Dinarello C A.
Proinflammatory cytokines.
Chest.
2000;
118
503-508
21
Hashimoto I, Doerschuk C M.
TNF and IL-1 are not required for the acute inflammatory response to S. pneumoniae in mice.
Am J Respir Crit Care Med.
2001;
163
A427
22
Frevert C W, Huang S, Danaee H et al..
Functional characterization of the rat chemokine KC and its importance in neutrophil recruitment in a rat model of pulmonary inflammation.
J Immunol.
1995;
154
335-344
23
Vik D, Amiguet P, Moffat G et al..
Structural features of the human C3 gene: intron/exon organization, transcriptional start site, and promoter region sequence.
Biochemistry.
1991;
30
1080-1085
24
Shimizu H, Yamamoto K.
NF-κB and C/EBP transcription factor families synergisitically function in mouse serum amyloid A gene expression induced by inflammatory cytokines.
Gene.
1994;
149
305-310
25
Moon M, Parikh A, Pritts T et al..
Complement component C3 production in IL-1β-stimulated human intestinal epithelial cells is blocked by NF-κB inhibitors and by transfection with ser 32/36 mutant IκBα.
J Surg Res.
1999;
82
48-55
26
Li Q, Verma I M.
NF-kappaB regulation in the immune system.
Nat Rev Immunol.
2002;
2
725-734
27
Hermanson O, Glass C K, Rosenfeld M G.
Nuclear receptor coregulators: multiple modes of modification.
Trends Endocrinol Metab.
2002;
13
55-60
28
Sadikot R T, Han W, Everhart M B et al..
Selective I kappa B kinase expression in airway epithelium generates neutrophilic lung inflammation.
J Immunol.
2003;
170
1091-1098
29
Mizgerd J P, Scott M L, Spieker M R, Doerschuk C M.
Functions of IκB proteins in inflammatory responses to E. coli LPS in mouse lungs.
Am J Respir Cell Mol Biol.
2002;
27
575-582
30
Schwartz M D, Moore E E, Moore F A et al..
Nuclear factor-kappa B is activated in alveolar macrophages from patients with acute respiratory distress syndrome.
Crit Care Med.
1996;
24
1285-1292
31
Moine P, McIntyre R, Schwartz M D et al..
NF-kappaB regulatory mechanisms in alveolar macrophages from patients with acute respiratory distress syndrome.
Shock.
2000;
13
85-91
32
Ouaaz F, Li M, Beg A A.
A critical role for the RelA subunit of nuclear factor kB in regulation of multiple immune-response genes and in Fas-induced cell death.
J Exp Med.
1999;
189
999-1004
33
Kunsch C, Rosen C A.
NF-κB subunit-specific regulation of the interleukin-8 promoter.
Mol Cell Biol.
1993;
13
6137-6146
34
Kumasaka T, Quinlan W M, Doyle N A et al..
The role of ICAM-1 in endotoxin-induced pneumonia evaluated using ICAM-1 antisense oligonucleotides, anti-ICAM-1 monoclonal antibodies, and ICAM-1 mutant mice.
J Clin Invest.
1996;
97
2362-2369
35
Schmal H, Shanley T P, Jones M L et al..
Role for macrophage inflammatory protein-2 in lipopolysaccharide-induced lung injury in rats.
J Immunol.
1996;
156
1963-1972
36
Beg A A, Sha W C, Bronson R T et al..
Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB.
Nature.
1995;
376
167-170
37
Alcamo E A, Mizgerd J P, Horwitz B H et al..
Targeted mutation of tumor necrosis factor 1 rescues the RelA-deficient mouse and reveals a critical role for NF-κB in leukocyte recruitment.
J Immunol.
2001;
167
1592-1600
38
Baer M, Dillner A, Schwartz R C et al..
Tumor necrosis factor alpha transcription in macrophages is attenuated by an autocrine factor that preferentially induces NF-kappaB p50.
Mol Cell Biol.
1998;
18
5678-5689
39
Beg A A, Sha W C, Bronson R T, Baltimore D.
Constitutive NF-κB activation, enhanced granulopoiesis, and neonatal lethality in IκBα-deficient mice.
Genes Dev.
1995;
9
2736-2746
40
Baer M, Dillner A, Schwartz R C et al..
Tumor necrosis factor alpha transcription in macrophages is attenuated by an autocrine factor that preferentially induces NF-kappaB p50.
Mol Cell Biol.
1998;
18
5678-5689
41
Bohuslav J, Kravchenko V K, Parry G CN et al..
Regulation of an essential innate immune response by the p50 subunit of NF-κB.
J Clin Invest.
1998;
102
1645-1652
42
Udalova I A, Richardson A, Denys A et al..
Functional consequences of a polymorphism affecting NF-kappaB p50-p50 binding to the TNF promoter region.
Mol Cell Biol.
2000;
20
9113-9119
43
Sheppard K A, Phelps K M, Williams A J et al..
Nuclear integration of glucocorticoid receptor and nuclear factor-kappaB signaling by CREB-binding protein and steroid receptor coactivator-1.
J Biol Chem.
1998;
273
29291-29294
44
McKay L I, Cidlowski J A.
CBP (CREB binding protein) integrates NF-kappaB (nuclear factor-kappaB) and glucocorticoid receptor physical interactions and antagonism.
Mol Endocrinol.
2000;
14
1222-1234
45
Rossi A, Kapahi P, Natoli G et al..
Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase.
Nature.
2000;
403
103-108
46
Ashburner B P, Westerheide S D, Baldwin Jr A S.
The p65 (RelA) subunit of NF-kappaB interacts with the histone deacetylase (HDAC) corepressors HDAC1 and HDAC2 to negatively regulate gene expression.
Mol Cell Biol.
2001;
21
7065-7077
47
Chen L, Fischle W, Verdin E, Greene W C.
Duration of nuclear NF-kappaB action regulated by reversible acetylation.
Science.
2001;
293
1653-1657
48
Sosic D, Richardson J A, Yu K et al..
Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity.
Cell.
2003;
112
169-180
49
Burns A R, Takei F, Doerschuk C M.
Quantitation of ICAM-1 expression in mouse lung during pneumonia.
J Immunol.
1994;
153
3189-3198
50
Kang B H, Manderschied B D, Huang Y C, Crapo J D, Chang L Y.
Contrasting response of lung parenchymal cells to instilled TNF alpha and IFN gamma: the inducibility of specific cell ICAM-1 in vivo.
Am J Respir Cell Mol Biol.
1996;
15
540-550
51
Doerschuk C M.
Mechanisms of leukocyte sequestration in inflamed lungs.
Microcirculation.
2001;
8
71-88
52
Doerschuk C M, Quinlan W M, Doyle N A et al..
The role of P-selectin and ICAM-1 in acute lung injury as determined using blocking antibodies and mutant mice.
J Immunol.
1996;
157
4609-4614
53
Kumasaka T, Quinlan W M, Doyle N A et al..
Role of the intercellular adhesion molecule-1 (ICAM-1) in endotoxin-induced pneumonia evaluated using ICAM-1 antisense oligonucleotides, anti-ICAM-1 monoclonal antibodies, and ICAM-1 mutant mice.
J Clin Invest.
1996;
97
2362-2369
54
Qin L, Quinlan W M, Doyle N A et al..
The roles of CD11/CD18 and ICAM-1 in acute Pseudomonas aeruginosa -induced pneumonia in mice.
J Immunol.
1996;
157
5016-5021
55
Barreiro O, Yanez-Mo M, Serrador J M et al..
Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes.
J Cell Biol.
2002;
157
1233-1245
56
Thompson P W, Randi A M, Ridley A J.
Intercellular adhesion molecule (ICAM)-1, but not ICAM-2, activates RhoA and stimulates c-fos and rhoA transcription in endothelial cells.
J Immunol.
2002;
169
1007-1013
57
Tilghman R W, Hoover R L.
The Src-cortactin pathway is required for clustering of E-selectin and ICAM-1 in endothelial cells.
FASEB J.
2002;
16
1257-1259
58
Hubbard A K, Rothlein R.
Intercellular adhesion molecule-1 (ICAM-1) expression and cell signaling cascades.
Free Radic Biol Med.
2000;
28
1379-1386
59
Tsakadze N L, Zhao A, D'Souza S E.
Interactions of intercellular adhesion molecule-1 with fibrinogen.
Trends Cardiovasc Med.
2002;
12
101-108
60
Wang Q, Doerschuk C M.
The signaling pathways induced by neutrophil-endothelial cell adhesion.
Antioxid Redox Signal.
2002;
4
39-47
61
Sans E, Delachanal E, Duperray A.
Analysis of the roles of ICAM-1 in neutrophil transmigration using a reconstituted mammalian cell expression model: implication of ICAM-1 cytoplasmic domain and Rho-dependent signaling pathway.
J Immunol.
2001;
166
544-551
62
Wang Q, Doerschuk C M.
Neutrophil-induced changes in the biomechanical properties of endothelial cells: the roles of ICAM-1 and oxidants.
J Immunol.
2000;
164
6487-6494
63
Wang Q, Doerschuk C M.
The p38 mitogen-activated protein kinase mediates cytoskeletal remodeling in pulmonary microvascular endothelial cells upon ICAM-1 ligation.
J Immunol.
2001;
166
6877-6884
64
Wang Q, Chiang E T, Lim M et al..
Changes in the biomechanical properties of neutrophils and endothelial cells during adhesion.
Blood.
2001;
97
660-668
65
Wang Q, Pfeiffer II G R, Stevens T, Doerschuk C M.
Lung microvascular and arterial endothelial cells differ in their responses to intercellular adhesion molecule-1 ligation.
Am J Respir Crit Care Med.
2002;
166
872-877
66
Walker D C, Behzad A R, Chu F.
Neutrophil migration through preexisting holes in the basal laminae of alveolar capillaries and epithelium during streptococcal pneumonia.
Microvasc Res.
1995;
50
397-416
67
Behzad A R, Chu F, Walker D C.
Fibroblasts are in a position to provide directional information to migrating neutrophils during pneumonia in rabbit lungs.
Microvasc Res.
1996;
51
303-316
68
Shen J, Ham R G, Karmiol S.
Expression of adhesion molecules in cultured human pulmonary microvascular endothelial cells.
Microvasc Res.
1995;
50
360-372
69
Cooper J A.
Effects of cytochalasin and phalloidin on actin.
J Cell Biol.
1987;
105
1473-1478
70
Bubb M R, Senderowicz A MJ, Sausville E A, Duncan K LK, Korn E D.
Jasplakinolide, a cytotoxic natural product, induces actin polymerization and competitively inhibits the binding of phalloidin to F-actin.
J Biol Chem.
1994;
269
14869-14871
71
Wojciak-Stothard B, Williams L, Ridley A J.
Monocyte adhesion and spreading on human endothelial cells is dependent on Rho-regulated receptor clustering.
J Cell Biol.
1999;
145
1293-1307
72
Huot J, Houle F, Marceau F, Landry J.
Oxidative stress-induced actin reorganization mediated by p38 mitogen-activated protein kinase/heat shock protein 27 pathways in vascular endothelial cells.
Circ Res.
1997;
80
383-392
73
Mueller G A, Quinlan W M, Doyle N A, Doerschuk C M.
The role of cytoskeletal proteins in neutrophil emigration during pneumonia in rabbits.
Am J Respir Crit Care Med.
1994;
150
455-461
74
Goldman G, Welbourn R, Klausner J M et al..
Attenuation of acid aspiration edema with phalloidin.
Am J Physiol.
1990;
259
L378-L383
75
Tasaka S, Mizgerd J P, Doerschuk C M.
Acute inflammatory response during streptococal pneumonia is reduced in interferon-γ deficient mice.
Am J Respir Crit Care Med.
1999;
159
A483
76
Tasaka S, Richer S E, Mizgerd J P, Doerschuk C M.
VLA-4 in CD18-independent neutrophil emigration during acute bacterial pneumonia in mice.
Am J Respir Crit Care Med.
2002;
166
53-60
77
Tasaka S, Qin L, Kutkoski G J, Albelda S M, DeLisser H M, Doerschuk C M.
The role of PECAM-1 (CD31) in neutrophil emigration during acute bacterial pneumonia in mice and rats.
Am J Respir Crit Care Med.
2003;
167
164-170
78
Wang Q, Teder P, Judd N P, Noble P W, Doerschuk C M.
CD44 deficiency leads to enhanced neutrophil migration and lung injury in E. coli pneumonia in mice.
Am J Pathol.
2002;
161
2219-2228
79
Ridger V C, Wagner B E, Wallace W AH, Hellewell P G.
Differential effects of CD18, CD29, and CD49 integrin subunit inhibition on neutrophil migration in pulmonary inflammation.
J Immunol.
2001;
166
3484-3490
Claire M DoerschukM.D.
Rainbow Babies and Children's Hospital, Room 787
11100 Euclid Ave., Cleveland
OH 44106
eMail: cmd22@po.cwru.edu