%PDF-1.6
%
1 0 obj
<>
endobj
2 0 obj
<>stream
Nuria Maicas, Johan van der Vlag, Janin Bublitz, Sandrine Florquin, Marinka Bakker-van Bebber, Charles A. Dinarello, Vivienne Verweij, Roos Masereeuw, Leo A. Joosten, Luuk B. Hilbrands
Human Alpha-1-Antitrypsin (hAAT) therapy reduces renal dysfunction and acute tubular necrosis in a murine model of bilateral kidney ischemia-reperfusion injury
www.plosone.org
www.plosone.org
endstream
endobj
3 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Annots 13 0 R/Contents 14 0 R/TrimBox[0 0 612 792]>>
endobj
13 0 obj
[15 0 R 16 0 R 17 0 R 18 0 R 19 0 R 20 0 R 21 0 R 22 0 R 23 0 R 24 0 R]
endobj
15 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168981.ref001)>>
endobj
16 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168981.ref002)>>
endobj
17 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168981.ref004)>>
endobj
18 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168981.ref005)>>
endobj
19 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168981.ref006)>>
endobj
20 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168981.ref007)>>
endobj
21 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168981.ref008)>>
endobj
22 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168981.ref009)>>
endobj
23 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168981.ref010)>>
endobj
24 0 obj
<>/Border[0 0 0]/Dest(Rpone.0168981.ref011)>>
endobj
14 0 obj
[25 0 R 26 0 R 27 0 R 28 0 R 29 0 R 30 0 R 31 0 R 32 0 R 33 0 R 34 0 R 35 0 R 36 0 R 37 0 R 38 0 R 39 0 R]
endobj
25 0 obj
<>stream
q
0.83 0.64 0.02 0 k
274.0535 635.9811 m
278.7591 635.9811 l
h
f*
502.6394 558.0283 m
507.4016 558.0283 l
h
f*
512.6173 558.0283 m
517.3795 558.0283 l
h
f*
499.0677 493.0016 m
503.7732 493.0016 l
h
f*
493.6252 480.0189 m
498.3874 480.0189 l
h
f*
502.8094 480.0189 m
507.5717 480.0189 l
h
f*
276.2079 466.9795 m
280.9701 466.9795 l
h
f*
454.2803 441.0142 m
459.0425 441.0142 l
h
f*
522.085 414.9921 m
531.6094 414.9921 l
h
f*
249.5622 350.022 m
259.0866 350.022 l
h
f*
0 g
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 706.0535 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Introduction)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 689.1023 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(Renal)Tj
2.4944 0 Td
(ischemia-reperfusion)Tj
8.6967 0 Td
(\(I/R\))Tj
2.194 0 Td
(injury)Tj
2.6475 0 Td
(is)Tj
0.8447 0 Td
(a)Tj
0.6577 0 Td
(frequent)Tj
3.6056 0 Td
(cause)Tj
2.3868 0 Td
(of)Tj
1.0148 0 Td
(acute)Tj
2.33 0 Td
(kidney)Tj
2.9367 0 Td
(injury)Tj
2.6475 0 Td
(\(AKI\))Tj
2.5966 0 Td
(in)Tj
1.0374 0 Td
(a)Tj
-36.0904 -1.3039 Td
(variety)Tj
2.9196 0 Td
(of)Tj
1.0205 0 Td
(clinical)Tj
3.0727 0 Td
(conditions)Tj
4.4787 0 Td
(such)Tj
2.058 0 Td
(as)Tj
1.0148 0 Td
(cardiac)Tj
3.1011 0 Td
(or)Tj
1.0998 0 Td
(aortic)Tj
2.5171 0 Td
(surgery)Tj
3.1975 0 Td
(and)Tj
1.7291 0 Td
(kidney)Tj
2.9367 0 Td
(transplantation,)Tj
6.5593 0 Td
(and)Tj
-35.7049 -1.2982 Td
(is)Tj
0.8447 0 Td
(associated)Tj
4.2576 0 Td
(with)Tj
2.0012 0 Td
(significant)Tj
4.388 0 Td
(morbidity)Tj
4.235 0 Td
(and)Tj
1.7348 0 Td
(mortality.)Tj
4.1385 0 Td
(Ischemic)Tj
3.8098 0 Td
(injury)Tj
2.6418 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(kidney)Tj
2.9367 0 Td
(causes)Tj
2.7496 0 Td
(the)Tj
-36.2265 -1.2983 Td
(release)Tj
2.9026 0 Td
(of)Tj
1.0148 0 Td
(damage-associated)Tj
7.7102 0 Td
(molecular)Tj
4.2179 0 Td
(patterns)Tj
3.4753 0 Td
(\(DAMPs\))Tj
4.1329 0 Td
(by)Tj
1.1792 0 Td
(impaired)Tj
3.8494 0 Td
(endothelial)Tj
4.6715 0 Td
(and)Tj
1.7291 0 Td
(tubu-)Tj
-34.8829 -1.3039 Td
(lar)Tj
1.2699 0 Td
(epithelial)Tj
3.8721 0 Td
(cells)Tj
1.9218 0 Td
([)Tj
0.83 0.64 0.02 0 k
(1)Tj
0 g
(].)Tj
1.5988 0 Td
(These)Tj
2.5681 0 Td
(DAMPs)Tj
3.4526 0 Td
(are)Tj
1.4457 0 Td
(rapidly)Tj
3.0387 0 Td
(sensed)Tj
2.8686 0 Td
(by)Tj
1.1793 0 Td
(pattern)Tj
3.1124 0 Td
(recognition)Tj
4.8472 0 Td
(receptors,)Tj
-31.1752 -1.2983 Td
(which)Tj
2.6475 0 Td
(together)Tj
3.5376 0 Td
(with)Tj
1.9956 0 Td
(the)Tj
1.4683 0 Td
(formation)Tj
4.2633 0 Td
(of)Tj
1.0148 0 Td
(reactive)Tj
3.3165 0 Td
(oxygen)Tj
3.0841 0 Td
(species)Tj
2.9934 0 Td
(after)Tj
2.0352 0 Td
(reperfusion)Tj
4.8302 0 Td
(lead)Tj
1.8482 0 Td
(to)Tj
1.0261 0 Td
(an)Tj
-34.0608 -1.2982 Td
(inflammatory)Tj
5.7089 0 Td
(response.)Tj
3.9571 0 Td
(Therefore,)Tj
4.3937 0 Td
(the)Tj
1.4683 0 Td
(focus)Tj
2.3244 0 Td
(of)Tj
1.0148 0 Td
(current)Tj
3.1862 0 Td
(research)Tj
3.5546 0 Td
(is)Tj
0.8504 0 Td
(to)Tj
1.0261 0 Td
(control)Tj
3.1181 0 Td
(innate)Tj
2.7439 0 Td
(immune)Tj
-33.3465 -1.304 Td
(pathways)Tj
3.9287 0 Td
(in)Tj
1.0375 0 Td
(order)Tj
2.4208 0 Td
(to)Tj
1.0261 0 Td
(reduce)Tj
2.914 0 Td
(I/R)Tj
1.5137 0 Td
(damage.)Tj
-11.6446 -1.2982 Td
(Alpha-1-antitrypsin)Tj
8.175 0 Td
(\(AAT\))Tj
2.88 0 Td
(is)Tj
0.8447 0 Td
(the)Tj
1.474 0 Td
(most)Tj
2.2054 0 Td
(abundant)Tj
4.0422 0 Td
(serum)Tj
2.7269 0 Td
(serine)Tj
2.6135 0 Td
(protease)Tj
3.5546 0 Td
(inhibitor,)Tj
4.0082 0 Td
(primarily)Tj
-33.7207 -1.2983 Td
(produced)Tj
4.0421 0 Td
(by)Tj
1.1849 0 Td
(the)Tj
1.4683 0 Td
(liver.)Tj
2.2111 0 Td
(Its)Tj
1.2188 0 Td
(main)Tj
2.2848 0 Td
(physiological)Tj
5.4481 0 Td
(role)Tj
1.7688 0 Td
(is)Tj
0.8447 0 Td
(to)Tj
1.0262 0 Td
(inhibit)Tj
2.9026 0 Td
(the)Tj
1.4684 0 Td
(activity)Tj
3.1181 0 Td
(of)Tj
1.0148 0 Td
(different)Tj
3.6566 0 Td
(endoge-)Tj
-33.6583 -1.2983 Td
(nous)Tj
2.1656 0 Td
(serine)Tj
2.6135 0 Td
(proteases,)Tj
4.1386 0 Td
(such)Tj
2.0636 0 Td
(as)Tj
1.0148 0 Td
(neutrophil-derived)Tj
7.8009 0 Td
(elastase)Tj
3.1975 0 Td
(and)Tj
1.7347 0 Td
(proteinase-3)Tj
5.1931 0 Td
([)Tj
0.83 0.64 0.02 0 k
(2)Tj
0 g
()Tj
0.83 0.64 0.02 0 k
(4)Tj
0 g
(].)Tj
2.5965 0 Td
(These)Tj
2.5682 0 Td
(pro-)Tj
-35.087 -1.3039 Td
(teolytic)Tj
3.135 0 Td
(enzymes)Tj
3.6681 0 Td
(contribute)Tj
4.388 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.474 0 Td
(inflammatory)Tj
5.7033 0 Td
(response)Tj
3.736 0 Td
(by)Tj
1.1792 0 Td
(activating)Tj
4.1102 0 Td
(pro-cytokines)Tj
5.7487 0 Td
(and)Tj
-34.1686 -1.2982 Td
(through)Tj
3.4412 0 Td
(the)Tj
1.474 0 Td
(formation)Tj
4.2576 0 Td
(of)Tj
1.0148 0 Td
(DAMPs.)Tj
3.6793 0 Td
(Due)Tj
1.9106 0 Td
(to)Tj
1.0205 0 Td
(its)Tj
1.1508 0 Td
(anti-protease)Tj
5.4538 0 Td
(activity,)Tj
3.3392 0 Td
(AAT)Tj
2.1997 0 Td
(can)Tj
1.6271 0 Td
(inhibit)Tj
2.9026 0 Td
(these)Tj
-33.4712 -1.2983 Td
(pathways,)Tj
4.1555 0 Td
(consequently)Tj
5.4879 0 Td
(exerting)Tj
3.4865 0 Td
(anti-inflammatory)Tj
7.6025 0 Td
(and)Tj
1.7348 0 Td
(tissue-protective)Tj
6.7918 0 Td
(effects.)Tj
2.948 0 Td
(During)Tj
-32.207 -1.3039 Td
(acute-phase)Tj
4.9322 0 Td
(responses,)Tj
4.3086 0 Td
(such)Tj
2.0523 0 Td
(as)Tj
1.0091 0 Td
(injury)Tj
2.6362 0 Td
(or)Tj
1.0942 0 Td
(infection,)Tj
4.0082 0 Td
(circulating)Tj
4.4843 0 Td
(AAT)Tj
2.1884 0 Td
(levels)Tj
2.3697 0 Td
(can)Tj
1.6158 0 Td
(increase)Tj
3.4639 0 Td
(approxi-)Tj
-34.1629 -1.2983 Td
(mately)Tj
2.8969 0 Td
(four-fold.)Tj
4.0592 0 Td
(In)Tj
1.1055 0 Td
(addition,)Tj
3.8211 0 Td
(AAT)Tj
2.1997 0 Td
(levels)Tj
2.3754 0 Td
(are)Tj
1.4513 0 Td
(up-regulated)Tj
5.3348 0 Td
(during)Tj
2.9253 0 Td
(hypoxia)Tj
3.3959 0 Td
([)Tj
0.83 0.64 0.02 0 k
(5)Tj
0 g
(])Tj
1.372 0 Td
(and)Tj
1.7291 0 Td
(are)Tj
1.4513 0 Td
(known)Tj
-34.1175 -1.2982 Td
(to)Tj
1.0261 0 Td
(be)Tj
1.1508 0 Td
(increased)Tj
3.9969 0 Td
(in)Tj
1.0374 0 Td
(plasma)Tj
3.0331 0 Td
(from)Tj
2.2053 0 Td
(patients)Tj
3.3676 0 Td
(with)Tj
1.9956 0 Td
(acute)Tj
2.33 0 Td
(myocardial)Tj
4.7055 0 Td
(infarction)Tj
4.1726 0 Td
([)Tj
0.83 0.64 0.02 0 k
(6)Tj
0 g
(,)Tj
0.83 0.64 0.02 0 k
1.2585 0 Td
(7)Tj
0 g
(])Tj
1.0375 0 Td
(and)Tj
1.7291 0 Td
(in)Tj
1.0375 0 Td
(urine)Tj
2.3584 0 Td
(of)Tj
-36.4419 -1.304 Td
(patients)Tj
3.3675 0 Td
(with)Tj
1.9956 0 Td
(AKI)Tj
1.9162 0 Td
([)Tj
0.83 0.64 0.02 0 k
(8)Tj
0 g
(],)Tj
1.6044 0 Td
(probably)Tj
3.7644 0 Td
(as)Tj
1.0148 0 Td
(an)Tj
1.2018 0 Td
(endogenous)Tj
5.057 0 Td
(protective)Tj
4.2066 0 Td
(response)Tj
3.736 0 Td
(against)Tj
3.0274 0 Td
(ischemic)Tj
3.7304 0 Td
(injury.)Tj
-34.6221 -1.2982 Td
(Accordingly,)Tj
5.3631 0 Td
(human)Tj
3.0784 0 Td
(AAT)Tj
2.1996 0 Td
(\(hAAT\))Tj
3.4073 0 Td
(given)Tj
2.3811 0 Td
(to)Tj
1.0204 0 Td
(mice)Tj
2.1543 0 Td
(during)Tj
2.931 0 Td
(acute)Tj
2.3244 0 Td
(myocardial)Tj
4.7055 0 Td
(I/R)Tj
1.5137 0 Td
(injury)Tj
2.6419 0 Td
(limited)Tj
-33.7207 -1.2983 Td
(the)Tj
1.4683 0 Td
(infarct)Tj
2.8516 0 Td
(size)Tj
1.6838 0 Td
(and)Tj
1.7291 0 Td
(protected)Tj
4.0138 0 Td
(from)Tj
2.2054 0 Td
(adverse)Tj
3.2145 0 Td
(cardiac)Tj
3.101 0 Td
(remodeling)Tj
4.8189 0 Td
([)Tj
0.83 0.64 0.02 0 k
(9)Tj
0 g
(].)Tj
1.6044 0 Td
(Moreover,)Tj
4.3937 0 Td
(there)Tj
2.262 0 Td
(is)Tj
0.8504 0 Td
(a)Tj
0.652 0 Td
(grow-)Tj
-34.8489 -1.2983 Td
(ing)Tj
1.5023 0 Td
(body)Tj
2.211 0 Td
(of)Tj
1.0148 0 Td
(evidence)Tj
3.7134 0 Td
(supporting)Tj
4.6034 0 Td
(the)Tj
1.4683 0 Td
(anti-inflammatory)Tj
7.6082 0 Td
(and)Tj
1.7291 0 Td
(cytoprotective)Tj
5.8904 0 Td
(effects)Tj
2.7212 0 Td
(of)Tj
1.0148 0 Td
(this)Tj
-33.4769 -1.3039 Td
(acute-phase)Tj
4.9379 0 Td
(reactant)Tj
3.4525 0 Td
(in)Tj
1.0375 0 Td
(a)Tj
0.652 0 Td
(wide)Tj
2.126 0 Td
(range)Tj
2.4604 0 Td
(of)Tj
/F10 1 Tf
1.0148 0 Td
[()12()]TJ
1.0148 0 Td
[()-13()14()7()20()]TJ
/F6 1 Tf
2.0466 0 Td
(and)Tj
/F10 1 Tf
1.7291 0 Td
[()12()]TJ
1.0148 0 Td
[()-13()15()3()]TJ
/F6 1 Tf
1.8199 0 Td
(experimental)Tj
5.4595 0 Td
(models)Tj
3.101 0 Td
([)Tj
0.83 0.64 0.02 0 k
(10)Tj
0 g
(].)Tj
2.0807 0 Td
(The)Tj
1.7801 0 Td
(cel-)Tj
-35.7276 -1.2982 Td
(lular)Tj
2.0466 0 Td
(targets)Tj
2.8686 0 Td
(of)Tj
1.0148 0 Td
(AAT)Tj
2.1997 0 Td
(mostly)Tj
2.9083 0 Td
(include)Tj
3.1861 0 Td
(cells)Tj
1.9162 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4684 0 Td
(innate)Tj
2.7439 0 Td
(immune)Tj
3.6226 0 Td
(system,)Tj
3.1635 0 Td
(such)Tj
2.0636 0 Td
(as)Tj
1.0148 0 Td
(neutrophils)Tj
4.8132 0 Td
(and)Tj
-36.0451 -1.2983 Td
(macrophages,)Tj
5.7259 0 Td
(as)Tj
1.0148 0 Td
(well)Tj
1.8198 0 Td
(as)Tj
1.0148 0 Td
(B)Tj
0.8051 0 Td
(lymphocytes)Tj
5.2497 0 Td
(and)Tj
1.7291 0 Td
(dendritic)Tj
3.8778 0 Td
(cells)Tj
1.9219 0 Td
(which)Tj
2.6475 0 Td
(are)Tj
1.4513 0 Td
(involved)Tj
3.6454 0 Td
(in)Tj
1.0374 0 Td
(the)Tj
1.4684 0 Td
(adaptive)Tj
-33.4089 -1.3039 Td
(immune)Tj
3.6226 0 Td
(response.)Tj
3.9628 0 Td
(However,)Tj
4.0762 0 Td
(its)Tj
1.1452 0 Td
(mechanism)Tj
4.8472 0 Td
(of)Tj
1.0148 0 Td
(action)Tj
2.6986 0 Td
(is)Tj
0.8447 0 Td
(not)Tj
1.576 0 Td
(completely)Tj
4.5808 0 Td
(understood,)Tj
5.0456 0 Td
(and)Tj
1.7292 0 Td
(some)Tj
-35.1437 -1.2983 Td
(studies)Tj
2.9876 0 Td
(suggest)Tj
3.1181 0 Td
(that)Tj
1.7802 0 Td
(the)Tj
1.4683 0 Td
(protective)Tj
4.2066 0 Td
(effects)Tj
2.7269 0 Td
(of)Tj
1.0148 0 Td
(AAT)Tj
2.1997 0 Td
(are)Tj
1.4456 0 Td
(independent)Tj
5.2725 0 Td
(of)Tj
1.0148 0 Td
(its)Tj
1.1508 0 Td
(serine)Tj
2.6135 0 Td
(protease)Tj
3.5547 0 Td
(inhibit-)Tj
-34.5541 -1.2983 Td
(ing)Tj
1.5023 0 Td
(activity)Tj
3.1124 0 Td
([)Tj
0.83 0.64 0.02 0 k
(11)Tj
0 g
(].)Tj
-3.4185 -1.3039 Td
(Given)Tj
2.6305 0 Td
(the)Tj
1.4683 0 Td
(pivotal)Tj
2.948 0 Td
(role)Tj
1.7689 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.4683 0 Td
(early)Tj
2.1486 0 Td
(inflammatory)Tj
5.709 0 Td
(response)Tj
3.736 0 Td
(in)Tj
1.0318 0 Td
(the)Tj
1.4684 0 Td
(pathogenesis)Tj
5.3574 0 Td
(of)Tj
1.0148 0 Td
(ischemic)Tj
-32.961 -1.2982 Td
(injury,)Tj
2.8686 0 Td
(we)Tj
1.3266 0 Td
(sought)Tj
2.9083 0 Td
(to)Tj
1.0262 0 Td
(investigate)Tj
4.4617 0 Td
(the)Tj
1.4683 0 Td
(effects)Tj
2.7269 0 Td
(of)Tj
1.0148 0 Td
(hAAT)Tj
2.7269 0 Td
(monotherapy)Tj
5.6296 0 Td
(on)Tj
1.2756 0 Td
(both)Tj
2.0579 0 Td
(AKI)Tj
1.9219 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.4684 0 Td
(kidney)Tj
-34.6108 -1.2983 Td
(repair)Tj
2.6021 0 Td
(process)Tj
3.1862 0 Td
(after)Tj
2.0352 0 Td
(ischemic)Tj
3.7304 0 Td
(insult.)Tj
2.6986 0 Td
(To)Tj
1.3379 0 Td
(address)Tj
3.2258 0 Td
(these)Tj
2.2507 0 Td
(issues)Tj
2.5228 0 Td
(we)Tj
1.3266 0 Td
(performed)Tj
4.4674 0 Td
(a)Tj
0.6576 0 Td
(mouse)Tj
2.8573 0 Td
(model)Tj
2.744 0 Td
(of)Tj
-35.6426 -1.3039 Td
(bilateral)Tj
3.4469 0 Td
(kidney)Tj
2.9366 0 Td
(I/R)Tj
1.5137 0 Td
(injury.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 269.0645 cm
BT
/F2 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Materials)Tj
4.5071 0 Td
(and)Tj
1.989 0 Td
(methods)Tj
/F0 1 Tf
-6.4961 -1.5023 Td
(Animals)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 234.0283 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(All)Tj
1.3889 0 Td
(animal)Tj
2.9594 0 Td
(procedures)Tj
4.6658 0 Td
(were)Tj
2.1089 0 Td
(approved)Tj
3.9628 0 Td
(by)Tj
1.1736 0 Td
(the)Tj
1.4626 0 Td
(Animal)Tj
3.2088 0 Td
(Ethics)Tj
2.6589 0 Td
(Committee)Tj
4.7339 0 Td
(of)Tj
1.0034 0 Td
(the)Tj
1.4627 0 Td
(Radboud)Tj
3.8607 0 Td
(univer-)Tj
-34.6504 -1.2982 Td
(sity)Tj
1.5987 0 Td
(\(Nijmegen,)Tj
4.7281 0 Td
(the)Tj
1.4684 0 Td
(Netherlands;)Tj
5.3461 0 Td
(RU-DEC)Tj
3.8948 0 Td
(2011049)Tj
4.0648 0 Td
(/)Tj
0.5499 0 Td
(2013198\).)Tj
4.6318 0 Td
(Handling)Tj
4.0252 0 Td
(of)Tj
1.0148 0 Td
(animals)Tj
3.3335 0 Td
(was)Tj
-34.6561 -1.2983 Td
(performed)Tj
4.4673 0 Td
(according)Tj
4.1896 0 Td
(to)Tj
1.0261 0 Td
(the)Tj
1.4684 0 Td
(guidelines)Tj
4.2746 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(Dutch)Tj
2.7326 0 Td
(Council)Tj
3.4015 0 Td
(for)Tj
1.389 0 Td
(Animal)Tj
3.2201 0 Td
(Care)Tj
2.109 0 Td
(and)Tj
1.7291 0 Td
(the)Tj
1.474 0 Td
(Euro-)Tj
-33.9701 -1.3039 Td
(pean)Tj
2.1429 0 Td
(Communities)Tj
5.7203 0 Td
(Council)Tj
3.4072 0 Td
(Directive)Tj
3.8835 0 Td
(\(86/609/EEC\).)Tj
5.964 0 Td
(Male)Tj
2.2167 0 Td
(C57Bl/6N)Tj
4.2009 0 Td
(mice)Tj
2.1543 0 Td
(\(Charles)Tj
3.5887 0 Td
(River,)Tj
-33.2785 -1.2983 Td
(Sulzfeld,)Tj
3.5943 0 Td
(Germany\))Tj
4.3256 0 Td
(were)Tj
2.1203 0 Td
(housed)Tj
3.0954 0 Td
(at)Tj
0.9525 0 Td
(the)Tj
1.4683 0 Td
(Central)Tj
3.2088 0 Td
(Animal)Tj
3.2201 0 Td
(Facility)Tj
3.1351 0 Td
(of)Tj
1.0148 0 Td
(the)Tj
1.474 0 Td
(Radboud)Tj
3.8721 0 Td
(University)Tj
-31.4813 -1.2982 Td
(under)Tj
2.6191 0 Td
(specific)Tj
3.1918 0 Td
(pathogen-free)Tj
5.794 0 Td
(conditions)Tj
4.4787 0 Td
(with)Tj
/F10 1 Tf
1.9956 0 Td
[()6()]TJ
1.2019 0 Td
[( )12()14(\n)11()14()7()12()]TJ
/F6 1 Tf
3.0727 0 Td
(food)Tj
2.0466 0 Td
(and)Tj
1.7291 0 Td
(water.)Tj
ET
Q
q
1 j
1 J
0 w
11.9999 0 0 11.9999 200.0125 139.011 cm
BT
/F0 1 Tf
1 TL
-0.0033 Tc
0 0 Td
(Experimental)Tj
5.9858 0 Td
(bilateral)Tj
3.6662 0 Td
(kidney)Tj
3.0709 0 Td
(I/R)Tj
1.4929 0 Td
(model)Tj
ET
Q
q
1 j
1 J
0 w
10 0 0 10 200.0125 122.0031 cm
BT
/F6 1 Tf
1 TL
-0.004 Tc
0 0 Td
(All)Tj
1.3946 0 Td
(surgical)Tj
3.3165 0 Td
(procedures)Tj
4.6715 0 Td
(were)Tj
2.1259 0 Td
(performed)Tj
4.4674 0 Td
(on)Tj
1.2756 0 Td
(8/9-week-old)Tj
5.5105 0 Td
(mice)Tj
2.1543 0 Td
(\(2228)Tj
2.9821 0 Td
(g\))Tj
1.0261 0 Td
(using)Tj
2.3867 0 Td
(standard)Tj
3.7247 0 Td
(asep-)Tj
-35.0359 -1.2982 Td
(tic)Tj
1.2075 0 Td
(surgical)Tj
3.3165 0 Td
(techniques,)Tj
4.7509 0 Td
(with)Tj
2.0012 0 Td
(all)Tj
1.1452 0 Td
(efforts)Tj
2.7552 0 Td
(to)Tj
1.0262 0 Td
(minimize)Tj
4.0478 0 Td
(suffering.)Tj
3.9855 0 Td
(Carprofen)Tj
4.3427 0 Td
([5)Tj
1.0374 0 Td
(mg/kg)Tj
2.795 0 Td
(body)Tj
2.2167 0 Td
(weight)Tj
-34.6278 -1.3039 Td
(\(b.w.\)])Tj
2.8799 0 Td
(was)Tj
1.7008 0 Td
(selected)Tj
3.3449 0 Td
(as)Tj
1.0148 0 Td
(a)Tj
0.6576 0 Td
(non-steroidal)Tj
5.6069 0 Td
(analgesic)Tj
3.8267 0 Td
(in)Tj
1.0318 0 Td
(all)Tj
1.1452 0 Td
(experimental)Tj
5.4595 0 Td
(groups)Tj
2.9707 0 Td
(and)Tj
1.7291 0 Td
(administered)Tj
-31.3679 -1.2983 Td
(subcutaneously)Tj
6.3665 0 Td
(\(s.c.\))Tj
2.1373 0 Td
(30)Tj
1.1679 0 Td
(min)Tj
1.8595 0 Td
(before)Tj
2.7383 0 Td
(the)Tj
1.4683 0 Td
(surgery,)Tj
3.4186 0 Td
(24h)Tj
1.7007 0 Td
(and)Tj
1.7292 0 Td
(48h)Tj
1.7007 0 Td
(after)Tj
2.0353 0 Td
(surgery.)Tj
3.4186 0 Td
(Anesthesia)Tj
4.5524 0 Td
(was)Tj
ET
Q
q
1 j
1 J
0 w
576 737.1 m
36 737.1 l
36 737.6 l
576 737.6 l
f*
36 741.2598 107.1496 23.6976 re
W* n
q
107.0929 0 0 23.6409 36 741.3165 cm
q
/I0 Do
Q
Q
Q
q
0 0 612 792 re
W* n
1 j
1 J
0 w
7.9999 0 0 7.9999 320.2582 745.7952 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(hAAT)Tj
2.6929 0 Td
(effects)Tj
3.1252 0 Td
(during)Tj
2.941 0 Td
(the)Tj
1.5874 0 Td
(early)Tj
2.3386 0 Td
(and)Tj
1.8567 0 Td
(recovery)Tj
3.9969 0 Td
(phase)Tj
2.8913 0 Td
(of)Tj
1.0418 0 Td
(renal)Tj
2.3953 0 Td
(I/R)Tj
1.4811 0 Td
(injury)Tj
2.5583 0 Td
(in)Tj
0.9779 0 Td
(mice)Tj
ET
Q
q
1 j
1 J
0 w
36 48.0002 m
576 48.0002 l
576 47.5002 l
36 47.5002 l
f*
7.9999 0 0 7.9999 36 36 cm
BT
/F0 1 Tf
1 TL
-0.005 Tc
0 0 Td
(PLOS)Tj
2.8559 0 Td
(ONE)Tj
2.3669 0 Td
(|)Tj
0.4748 0 Td
(DOI:10.137)Tj
5.0387 0 Td
(1/journal.po)Tj
5.1236 0 Td
(ne.0168)Tj
3.5434 0 Td
(981)Tj
2.6362 0 Td
(February)Tj
4.1599 0 Td
(24,)Tj
1.5874 0 Td
(2017)Tj
37.3538 0 Td
(2)Tj
0.7654 0 Td
(/)Tj
0.496 0 Td
(18)Tj
/F7 1 Tf
-0.025 Tc
-66.402 84.0904 Td
(Competing)Tj
4.3795 0 Td
(interests)Tj
3.3307 0 Td
(:)Tj
/F8 1 Tf
0.4819 0 Td
(The)Tj
1.5875 0 Td
(authors)Tj
3.0401 0 Td
(have)Tj
1.963 0 Td
(declared)Tj
-14.7827 -1.3748 Td
(that)Tj
1.6228 0 Td
(no)Tj
1.1693 0 Td
(competing)Tj
4.1599 0 Td
(interests)Tj
ET
endstream
endobj
26 0 obj
<>stream
endstream
endobj
27 0 obj
<>stream
endstream
endobj
28 0 obj
<>stream
endstream
endobj
29 0 obj
<>stream
endstream
endobj
30 0 obj
<>stream
endstream
endobj
31 0 obj
<>stream
endstream
endobj
32 0 obj
<>stream
endstream
endobj
33 0 obj
<>stream
endstream
endobj
34 0 obj
<>stream
endstream
endobj
35 0 obj
<>stream
endstream
endobj
36 0 obj
<>stream
endstream
endobj
37 0 obj
<>stream
endstream
endobj
38 0 obj
<>stream
endstream
endobj
39 0 obj
<>stream
BT
10.3394 82.7156 Td
(exist.)Tj
ET
Q
endstream
endobj
40 0 obj
<>/XObject<>>>/CropBox[0 0 612 792]/MediaBox[0 0 612 792]/Parent 12 0 R/Contents 45 0 R/TrimBox[0 0 612 792]>>
endobj
41 0 obj
<>
endobj
46 0 obj
<>
endobj
47 0 obj
<>stream
%!PS-AdobeFont-1.0
11 dict begin
/FontName /TeX_CM_Maths_Symbols def
/FontType 1 def
/FontBBox {-20 -958 1114 770} readonly def
/FontMatrix [0.001 0 0 0.001 0 0] readonly def
/PaintType 0 def
/FontInfo 8 dict dup begin
/FullName (TeX_CM_Maths_Symbols) readonly def
/BaseFontName (TeX_CM_Maths_Symbols) def
end def
/Encoding 256 array
0 1 255 {1 index exch /.notdef put} for
dup 0 /C0 put
dup 1 /C1 put
dup 2 /C2 put
dup 3 /C3 put
dup 4 /C4 put
dup 5 /C5 put
dup 6 /C6 put
dup 7 /C7 put
dup 8 /C8 put
dup 9 /C9 put
dup 10 /C10 put
dup 11 /C11 put
dup 12 /C12 put
dup 13 /C13 put
dup 14 /C14 put
dup 15 /C15 put
dup 16 /C16 put
dup 17 /C17 put
dup 18 /C18 put
dup 19 /C19 put
dup 20 /C20 put
dup 21 /C21 put
dup 22 /C22 put
dup 23 /C23 put
dup 24 /C24 put
dup 25 /C25 put
dup 26 /C26 put
dup 27 /C27 put
dup 28 /C28 put
dup 29 /C29 put
dup 30 /C30 put
dup 31 /C31 put
dup 32 /space put
dup 33 /exclam put
dup 34 /quotedbl put
dup 35 /numbersign put
dup 36 /dollar put
dup 37 /percent put
dup 38 /ampersand put
dup 39 /quoteright put
dup 40 /parenleft put
dup 41 /parenright put
dup 42 /asterisk put
dup 43 /plus put
dup 44 /comma put
dup 45 /hyphen put
dup 46 /period put
dup 47 /slash put
dup 48 /zero put
dup 49 /one put
dup 50 /two put
dup 51 /three put
dup 52 /four put
dup 53 /five put
dup 54 /six put
dup 55 /seven put
dup 56 /eight put
dup 57 /nine put
dup 58 /colon put
dup 59 /semicolon put
dup 60 /less put
dup 61 /equal put
dup 62 /greater put
dup 63 /question put
dup 64 /at put
dup 65 /A put
dup 66 /B put
dup 67 /C put
dup 68 /D put
dup 69 /E put
dup 70 /F put
dup 71 /G put
dup 72 /H put
dup 73 /I put
dup 74 /J put
dup 75 /K put
dup 76 /L put
dup 77 /M put
dup 78 /N put
dup 79 /O put
dup 80 /P put
dup 81 /Q put
dup 82 /R put
dup 83 /S put
dup 84 /T put
dup 85 /U put
dup 86 /V put
dup 87 /W put
dup 88 /X put
dup 89 /Y put
dup 90 /Z put
dup 91 /bracketleft put
dup 92 /backslash put
dup 93 /bracketright put
dup 94 /asciicircum put
dup 95 /underscore put
dup 96 /quoteleft put
dup 97 /a put
dup 98 /b put
dup 99 /c put
dup 100 /d put
dup 101 /e put
dup 102 /f put
dup 103 /g put
dup 104 /h put
dup 105 /i put
dup 106 /j put
dup 107 /k put
dup 108 /l put
dup 109 /m put
dup 110 /n put
dup 111 /o put
dup 112 /p put
dup 113 /q put
dup 114 /r put
dup 115 /s put
dup 116 /t put
dup 117 /u put
dup 118 /v put
dup 119 /w put
dup 120 /x put
dup 121 /y put
dup 122 /z put
dup 123 /braceleft put
dup 124 /bar put
dup 125 /braceright put
dup 126 /asciitilde put
dup 127 /Euro put
dup 128 /ff put
dup 129 /ffi put
dup 130 /ffl put
dup 131 /C131 put
dup 132 /Eth put
dup 133 /eth put
dup 134 /Thorn put
dup 135 /thorn put
dup 136 /onequarter put
dup 137 /onehalf put
dup 138 /C138 put
readonly def
currentdict end
currentfile eexec
M#1H5 J6o\&rtS(#v\0\V7Fe༙OYx5-cY9^%Y6
(efIOldN"wȰ;)UƽoFg/rvV$JS8_oc@
o9-eGJp}[Do]mN=4*{ܯq=eU^t6¤(HwK7X7
Mr:E%]3<Ӝ$wrAQ4ADt%̏>E hAجm*pu@>#6aZi}NRmƼ%
,OgX' EX?ڞ\#JEG<IXS}Eh[ş8ї48ٶ.w4bJ?_nfulqD?둓\C%+' { L9K7isW+ӕ(6oɧVҺlS;5K
Z%.oQՕW*9Qk_S+B-}%lYC@WP0b\KKdi>t,n_S[ '9`-z+cڦEb#c@;yɸoAT O_H~i -6ϰ豟Ae&BF+
wNX!=hhUF8(hZ6pgJc m'9dx*^wXc
գ<.쯶c ln)/LvXY2jbF:ȸ3'>\Ȥmzj,!:ZK' (q/ -&&S ؤ-bm KQSxLGu `D3yԱKaVMU§ %iq5%s 2SdR#ho45H.4TdՊa<K>BqG- Ao, (e&F2gG`z8*༠&
x#B
B;8!93~T/ \>nLazCSKm~,!_<ӾX@X@N2vEt בFmBYa wRG[i;+oM+%(8 jԀlIW>t