Substance P in polymicrobial sepsis: molecular fingerprint of lung injury in preprotachykinin-A-/- mice.
Deletion of mouse preprotachykinin-A (PPTA), which encodes mainly for neuropeptide substance P, has been shown to protect against lung injury and mortality in sepsis. This study explored microarray-based differential gene expression profiles in mouse lung tissue 8 h after inducing microbial sepsis and the effect of PPTA gene deletion. A range of genes differentially expressed (more than two-fold) in microarray analysis was assessed, comparing wild-type and PPTA-knockout septic mice with their respective sham controls, and the data were further validated. Genetic deletion of substance P resulted in a significantly different expression profile of genes involved in inflammation and immunomodulation after the induction of sepsis, compared with wild-type mice. Interestingly, apart from the various proinflammatory mediators, the antiinflammatory cytokine interleukin-1 receptor antagonist gene (IL1RN) was also elevated much more in PPTA(-/-) septic mice. In addition, semiquantitative RT-PCR analysis supported the microarray data. The microarray data imply that the elevated levels of inflammatory gene expression in the early stages of sepsis in PPTA-knockout mice are possibly aimed to resolve the infection without excessive immunosuppression. As scientists are divided over the effects of pro- and antiinflammatory mediators in sepsis, it seems prudent to define the status depending on a complete genome profile. This is the first report exploring pulmonary gene expression profiles using microarray analysis in PPTA-knockout mice subjected to cecal ligation and puncture-induced sepsis and providing additional biological insight into the protection received against lung injury and mortality.
Hegde
Akhil
A
Cardiovascular Biology Program, Department of Pharmacology, Yong Loo Lin School of Medicine,National University of Singapore, Singapore.
Tamizhselvi
Ramasamy
R
Manikandan
Jayapal
J
Melendez
Alirio J
AJ
Moochhala
Shabbir M
SM
Bhatia
Madhav
M
D000704:Analysis of Variance; D000818:Animals; D016470:Bacteremia / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D008171:Lung Diseases / Q000235:genetics / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011498:Protein Precursors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015320:Tachykinins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism
D018925:Chemokines; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D011498:Protein Precursors; D015320:Tachykinins; C044206:preprotachykinin
J Am Coll Surg. 2006 Nov;203(5):585-598
17084318
J Leukoc Biol. 2007 Sep;82(3):678-85
17565047
Antimicrob Agents Chemother. 1995 Jun;39(6):1336-40
7574526
J Leukoc Biol. 2002 Dec;72(6):1190-7
12488501
J Leukoc Biol. 2004 Jan;75(1):39-48
12960280
J Leukoc Biol. 2008 Feb;83(2):288-95
17998302
Infect Dis Clin North Am. 1999 Jun;13(2):413-26, ix
10340175
Recent Pat Inflamm Allergy Drug Discov. 2009 Jan;3(1):26-32
19149743
Am J Physiol Lung Cell Mol Physiol. 2005 Apr;288(4):L633-40
15579629
Nat Genet. 2001 Dec;29(4):365-71
11726920
Crit Care Med. 2003 May;31(5):1560-7
12771633
Scand J Infect Dis. 2003;35(9):535-44
14620132
J Pathol. 2008 Jan;214(2):211-23
18161754
J Immunol. 2003 Oct 1;171(7):3775-84
14500678
Blood. 1996 May 15;87(10):4261-75
8639785
N Engl J Med. 2006 Aug 10;355(6):581-92
16899778
Immunol Res. 2001;24(3):273-87
11817325
J Immunol. 2006 Mar 15;176(6):3813-20
16517752
Nat Cell Biol. 2001 Aug;3(8):E190-5
11483980
Infect Immun. 1997 Sep;65(9):3847-51
9284162
N Engl J Med. 2003 Jan 9;348(2):138-50
12519925
J Immunol. 2000 May 15;164(10):5362-8
10799899
J Leukoc Biol. 2003 Sep;74(3):448-55
12949249
Inflamm Allergy Drug Targets. 2007 Jun;6(2):91-100
17692032
Crit Care Med. 2009 Jan;37(1):291-304
19050640
J Inflamm (Lond). 2006 Jan 27;3:1
16441890
Am J Physiol Gastrointest Liver Physiol. 2003 May;284(5):G830-6
12684214
J Immunol. 2004 Dec 1;173(11):6938-48
15557190
Am J Pathol. 2007 May;170(5):1435-44
17456750
Infect Immun. 1998 Aug;66(8):3569-78
9673235
J Immunol. 2006 Aug 1;177(3):1967-74
16849510
J Immunol. 2005 Aug 15;175(4):2589-97
16081833
Am J Physiol Regul Integr Comp Physiol. 2001 Aug;281(2):R654-60
11448871