2019 Sc ie ntific Re tre a t F RI DAY, APRI L 26, 2019 DI - - PowerPoint PPT Presentation

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2019 Sc ie ntific Re tre a t F RI DAY, APRI L 26, 2019 DI - - PowerPoint PPT Presentation

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2019 Sc ie ntific Re tre a t F RI DAY, APRI L 26, 2019 DI SCOVE RY WORL D PAVI L I ON RE PROGRAMMI NG NE UT ROPHI L S T O CONT ROL T I SSUE I NJURY Benjamin Gantner, PhD Assistant Professor of Medicine, Division of

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SLIDE 1

2019 Sc ie ntific Re tre a t

F RI DAY, APRI L 26, 2019 DI SCOVE RY WORL D PAVI L I ON

T

  • g e the r, T

a king o n Ca nc e r’ s T

  • ug he st Cha lle ng e s

RE PROGRAMMI NG NE UT ROPHI L S T O CONT ROL T I SSUE I NJURY

Benjamin Gantner, PhD Assistant Professor of Medicine, Division of Endocrinology Medical College of Wisconsin

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SLIDE 2

NE UT ROPHI L S SE ARCH F OR I NJURY AND I NF E CT I ON

?

Damage-Associated Stimuli:

  • Signs of Injury
  • Mitochondrial DNA
  • Mitochondrial Peptides (Formylated)
  • Purinergic stimuli (ATP, etc.)

Bacterial Stimuli:

  • Lipopolysaccharide (Gram Negatives)
  • Lipopeptides
  • Peptidoglycans
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SLIDE 3

NE UT ROPHI L S F I ND T UMORS…

?

Damage-Associated Stimuli:

  • Signs of Injury
  • Mitochondrial DNA
  • Mitochondrial Peptides (Formylated)
  • Purinergic stimuli (ATP, etc.)

Bacterial Stimuli:

  • Lipopolysaccharide (Gram Negatives)
  • Lipopeptides
  • Peptidoglycans
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SLIDE 4

I NT RAVI T AL I MAGI NG OF VE NT I L AT E D L UNGS

Cove

  • verslip

Vacuum Lung ng Vacuum

CANCE R COL L ABORAT I VE

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SLIDE 5

SURGI CAL PRE PARAT I ON F OR L UNG I MAGI NG

Cove

  • verslip

Vacuum Lung ng Vacuum

CANCE R COL L ABORAT I VE

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SLIDE 6

* Omiecinski, U.W. Seattle

Vascular Casts

40 second projection

CANCE R COL L ABORAT I VE

I NT RAVI T AL I MAGI NG OF VE NT I L AT E D L UNGS

  • Ne utro phils c ra wling in no rma l lung
  • 5 minute s re a l time o r ~600 b re a ths

100µm 100µm

Albumin Neutrophil

Unaligned Stabilized

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SLIDE 7

I MAGI NG WI T H CE L L UL AR RE SOL UT I ON

100µm 100µm

4 8 10 20 30 40 40 80

p < 0.000001 p < 0.001 Hours after aerosol LPS delivery Neutrophil speed (µm/min)

Neutrophil c crawling ng veloci city ( (µm µm/m /min)

Hours a s after er A Aerosol L LPS

Septal Thicknes ess ( (µm) Alveolar ar A Area ( a (µm2)

10 20 30 40 50 60 70 80 90 100

Unstim LPS p < 0.05

10 20 30 40 50 60 70 80 90 Unstim LPS

p < 0.02

CANCE R COL L ABORAT I VE

  • Ne utro phils a dhe re to infla me d c a pilla rie s
  • 5 minute s re a l time o r ~600 b re a ths

Albumin Neutrophil

Unaligned Stabilized

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SLIDE 8

NI T RI C OXI DE SYNT HASE 1 PROMOT E S SE PT I C L E T HAL I T Y AND L UNG I NJURY

24 48 72 96 20 40 60 80 100 WT NOS1-/- NOS2-/- (n=42) (n=40) (n=32) NOS3-/- (n=31) P<0.0005 Hours after LPS Percent survival

CANCE R COL L ABORAT I VE

NOS1 (Neuronal NOS)

(Neuronal NOS) (Inducible NOS) (Endothelial NOS) nNOS iNOS eNOS

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SLIDE 9

WT NOS1-/-

Untreated LPS, 8h 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Lung Filtration Coefficient ml/min/cm H2O/g LPS: - + - +

** WT NOS1-/-

NI T RI C OXI DE SYNT HASE 1 PROMOT E S SE PT I C L E T HAL I T Y AND L UNG I NJURY

24 48 72 96 20 40 60 80 100 WT NOS1-/- NOS2-/- (n=42) (n=40) (n=32) NOS3-/- (n=31) P<0.0005 Hours after LPS Percent survival

CANCE R COL L ABORAT I VE

NOS1 (Neuronal NOS)

(Neuronal NOS) (Inducible NOS) (Endothelial NOS) nNOS iNOS eNOS

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SLIDE 10

WT NOS1-/-

Untreated LPS, 8h 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Lung Filtration Coefficient ml/min/cm H2O/g LPS: - + - +

** WT NOS1-/-

NI T RI C OXI DE SYNT HASE 1 PROMOT E S SE PT I C L E T HAL I T Y AND L UNG I NJURY

24 48 72 96 20 40 60 80 100 WT NOS1-/- NOS2-/- (n=42) (n=40) (n=32) NOS3-/- (n=31) P<0.0005 Hours after LPS Percent survival

*Baig, et al, 2015, J Exp Med

CANCE R COL L ABORAT I VE

NOS1 (Neuronal NOS)

(Neuronal NOS) (Inducible NOS) (Endothelial NOS) nNOS iNOS eNOS

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SLIDE 11

I NACT I VAT I ON OF NOS1 L E ADS T O NON-I NJURI OUS SWARMI NG AND BL OCK S I NF L AMMAT ORY VASCUL AR I NJURY

  • 6 hours after LPS
  • 30mg/kg, i.p.
  • 5 minute time

lapse

WT NOS1-/-

100µm

CANCE R COL L ABORAT I VE

Albumin Neutrophli

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SLIDE 12

CANCE R COL L ABORAT I VE

Endot

  • thel

elial Neutrop

  • phil

Alb lbumin in

NOS1 DRI VE S I NJURY, NOT NE UT ROPHI L RE CRUI T ME NT

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SLIDE 13

NOS1 I S NOT RE QUI RE D F OR NE UT ROPHI L SE NT I NE L F UNCT I ON OR PHAGOCYT OSI S

CANCE R COL L ABORAT I VE

Endot

  • thel

elial Neutrop

  • phil

Alb lbumin in Latex B Bea eads 5 5 min. r rea eal time

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SLIDE 14

RE PROGRAMMI NG NE UT ROPHI L S I N T UMORS?

Damage-Associated Stimuli:

  • Signs of Injury
  • Mitochondrial DNA
  • Mitochondrial Peptides (Formylated)
  • Purinergic stimuli (ATP, etc.)

Bacterial Stimuli:

  • Lipopolysaccharide (Gram Negatives)
  • Lipopeptides
  • Peptidoglycans
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SLIDE 15

CANCE R COL L ABORAT I VE

mc w.e du/ de pa rtme nts/ c a nc e r-c e nte r @ MCWCa nc e rCe nte r

I f yo u wa nt to g o fa st, g o a lo ne . I f yo u wa nt to g o fa r, g o to g e the r.

– Afric a n Pro ve rb

ACKNOWLEDGEMENTS

  • Steve Vogel
  • Peter Toth
  • Richard Minshall
  • Maricela Castellon
  • Suellen D`Arc dos

Santos Oliveira

  • Rebecca Shilling
  • Mao Mao
  • Sofia Zaichick
  • Saqib Baig
  • Andre de Abreu
  • Farnaz Bakhshi
  • Peter Hart
  • Jing Deng
  • John Christman
  • Marcelo Bonini
  • Chenxia He

Support from:

  • Advancing a Healthier Wisconsin

Endowment – Research and Education Program

  • Cancer Center Pilot Funding
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SLIDE 16