Re: Interesting article: cystic fibrosis pig model

[Guest guest]

Dave, how interesting.

How do they give a mouse Colitis? What do they the mouse? It sounds like colitis causes PSC. It seems like many people who have PSC have colitis. My dad who has psc does not have colitis or perhaps he does without the symtoms. PSC is not reverseable right? Would treating Colitis stop further progression of PSC? Sorry about all of these questions.

Lori A.

"Aggressively Pursuing Solutions To Your Real Estate Needs!"

First Weber Group

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1507 E. Sunset Drive

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Interesting article: cystic fibrosis pig model

This article struck me as interesting. It may prove to be a better model of cystic fibrosis (caused by CFTR gene deficiency) than the mouse model. I feel sorry for the piggies, but I hope that they will help accelerate research to provide better treatments for cystic fibrosis patients. Maybe this will also be helpful in PSC because the liver pathology in this new pig model looks very much like human primary sclerosing cholangitis. In the mouse model, sclerosing cholangitis only develops after the mice are given colitis. In this new pig model, the bile-duct inflammation is evident soon after birth. ____________ _________ _________ _________ _____Science 2008 Sep 26;321(5897) :1837-41.Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, Rogan MP, Pezzulo AA, Karp PH, Itani OA, Kabel

AC, Wohlford-Lenane CL, GJ, Hanfland RA, TL, M, Wax D, CN, Rieke A, Whitworth K, Uc A, Starner TD, Brogden KA, Shilyansky J, McCray PB Jr, Zabner J, Prather RS, Welsh MJ.Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles.

Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The pig model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of strategies for prevention and treatment. PMID: 18818360.____________ _________ _________ _________ _____Dave (father of (23); PSC 07/03; UC 08/03)

[Guest guest]

Dave, how interesting.

How do they give a mouse Colitis? What do they the mouse? It sounds like colitis causes PSC. It seems like many people who have PSC have colitis. My dad who has psc does not have colitis or perhaps he does without the symtoms. PSC is not reverseable right? Would treating Colitis stop further progression of PSC? Sorry about all of these questions.

Lori A.

"Aggressively Pursuing Solutions To Your Real Estate Needs!"

First Weber Group

Cell:

1507 E. Sunset Drive

Waukesha, WI 53189

LoriUSA@...

www.Lori.FirstWeber.com

Interesting article: cystic fibrosis pig model

This article struck me as interesting. It may prove to be a better model of cystic fibrosis (caused by CFTR gene deficiency) than the mouse model. I feel sorry for the piggies, but I hope that they will help accelerate research to provide better treatments for cystic fibrosis patients. Maybe this will also be helpful in PSC because the liver pathology in this new pig model looks very much like human primary sclerosing cholangitis. In the mouse model, sclerosing cholangitis only develops after the mice are given colitis. In this new pig model, the bile-duct inflammation is evident soon after birth. ____________ _________ _________ _________ _____Science 2008 Sep 26;321(5897) :1837-41.Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, Rogan MP, Pezzulo AA, Karp PH, Itani OA, Kabel

AC, Wohlford-Lenane CL, GJ, Hanfland RA, TL, M, Wax D, CN, Rieke A, Whitworth K, Uc A, Starner TD, Brogden KA, Shilyansky J, McCray PB Jr, Zabner J, Prather RS, Welsh MJ.Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.Almost two decades after CFTR was identified as the gene responsible for cystic fibrosis (CF), we still lack answers to many questions about the pathogenesis of the disease, and it remains incurable. Mice with a disrupted CFTR gene have greatly facilitated CF studies, but the mutant mice do not develop the characteristic manifestations of human CF, including abnormalities of the pancreas, lung, intestine, liver, and other organs. Because pigs share many anatomical and physiological features with humans, we generated pigs with a targeted disruption of both CFTR alleles.

Newborn pigs lacking CFTR exhibited defective chloride transport and developed meconium ileus, exocrine pancreatic destruction, and focal biliary cirrhosis, replicating abnormalities seen in newborn humans with CF. The pig model may provide opportunities to address persistent questions about CF pathogenesis and accelerate discovery of strategies for prevention and treatment. PMID: 18818360.____________ _________ _________ _________ _____Dave (father of (23); PSC 07/03; UC 08/03)

[Guest guest]

Hi Lori;

They give the cystic fibrosis mutant mice oral dextran to induce

colitis. This causes bile-duct injury closely resembling human PSC.

The bile-duct injury is blocked by feeding the mice docosahexaenoic

acid (DHA), an anti-inflammatory omega-3 fatty acid found at high

levels in fish oil:

Blanco PG, Zaman MM, Junaidi O, Sheth S, Yantiss RK, Nasser IA,

Freedman SD 2004 Induction of colitis in cftr-/- mice results in bile

duct injury. Am. J. Physiol. Gastrointest. Liver Physiol. 287: G491-

G496.

http://www.ncbi.nlm.nih.gov/pubmed/15064232

If you follow the link to the full paper,

http://ajpgi.physiology.org/cgi/content/full/287/2/G491

you'll also see that the other omega-3 fatty acid found in fish oil,

eicosapentaenoic acid (EPA), is also pretty effective in reducing

bile-duct injury, although the authors conclude that it is not

statistically significant (see Fig. 4).

The more recent research from Freedman's group suggests that the DHA

is activating and/or inducing the nuclear receptor PPAR-alpha (and

perhaps also RXR-alpha) to prevent bile-duct injury in these mice.

Pall H, Zaman MM, Andersson C, Freedman SD 2006 Decreased peroxisome

proliferator activated receptor alpha is associated with bile duct

injury in cystic fibrosis transmembrane conductance regulator-/-

mice. J. Pediatr. Gastroenterol. Nutr. 42: 275-281.

http://www.ncbi.nlm.nih.gov/pubmed/16540796

Because children with PSC seem to have a defect in cystic fibrosis

gene function:

Pall H, Zielenski J, Jonas MM, Dasilva DA, Potvin KM, Yuan, XW, Huang

Q, Freedman SD 2007 Primary sclerosing cholangitis in childhood is

associated with abnormalities in cystic fibrosis-mediated chloride

channel function. J. Pediatr. 151: 255-259.

http://www.ncbi.nlm.nih.gov/pubmed/17719933

this is the rationale for the ongoing trial of DHA in the treatment

of PSC:

http://www.clinicaltrials.gov/ct2/show/NCT00325013

We'll have more to say about the preliminary results from this trial

in a few days.

If you look up CFTR in the Online Mendelian Inheritance in Man

database, it has this to say about CFTR and PSC:

" Primary sclerosing cholangitis (PSC), a slowly progressive

cholestatic liver disease characterized by fibroobliterative

inflammation of the biliary tract, leads to cirrhosis and portal

hypertension and is a major indication for liver transplantation.

Sheth et al. (2003) stated that 75 to 80% of cases were associated

with inflammatory bowel disease (IBD; 266600) and that 2.5 to 7.5% of

patients with IBD develop PSC (Lee and Kaplan, 1995). Sheth et al.

(2003) hypothesized that dysfunction of CFTR may explain why a subset

of patients with IBD develop PSC. They prospectively evaluated CFTR

genotype and phenotype in 19 patients with PSC compared with 18

patients with IBD and no liver disease, 17 with primary biliary

cirrhosis (PBC; 109720), 81 with CF, and 51 healthy controls. They

found an increased prevalence of CFTR abnormalities in heterozygous

state in PSC as demonstrated by molecular and functional analyses,

and concluded that these abnormalities may contribute to the

development of PSC in a subset of patients with IBD. Eighty-nine

percent of PSC patients carried genotypes containing the 1540G

variant (602421.0023) resulting in decreased functional CFTR compared

with 57% of disease controls (P = 0.03). Only 1 of 19 PSC patients

had neither a CFTR mutation nor the 1540G variant. CFTR chloride

channel function assessed by nasal potential difference testing

demonstrated a reduced median isoproterenol response in PSC patients

compared with disease controls and healthy controls. "

http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602421

It's not clear whether the bile-duct injury in the mouse model can be

reversed once it has taken place. If the colitis is causing a damage

to the intestinal barrier that then allows bacterial toxins and/or

bacteria to enter the blood stream and reach the liver, then it might

be expected that stopping the intestinal inflammation might delay

progression of the liver disease? But others suggest that the course

of PSC is independent of intestinal inflammation.

I hope this answers all of your questions.

Best regards,

Dave

(father of (23); PSC 07/03; UC 08/03)

>

> Dave, how interesting. 

>

> How do they give a mouse Colitis? What do they the mouse?  It

sounds like colitis causes PSC.  It seems like many people who have

PSC have colitis.  My dad who has psc does not have colitis or

perhaps he does without the symtoms.  PSC is not reverseable

right?  Would treating Colitis stop further progression of

PSC?  Sorry about all of these questions.

>  

> Lori A.

[Guest guest]

Hi Lori;

Yes, the DHA (and to a lesser extent EPA) largely prevents the bile-

duct injury when the cftr (-/-) mice are given colitis.

My son has been taking fish oils for the past 3 years and we are

hoping that this may delay PSC disease progression ... assuming that

similar mechanisms may be involved? Certainly his liver function

tests are now the best they have been since diagnosis (5 years ago),

and this is all that we have to go on at present.

I believe that others in the support group have been taking either

DHA alone, or fish oils (combination of EPA and DHA) and have

reported improvements in their liver function tests (e.g. reduced

serum alkaline phosphatase). Perhaps others will chime in on this

topic?

I am not in the medical field ... actually I'm a plant biochemist.

But I have read a lot about PSC, IBD, and autoimmune diseases in the

past 5 years, and most everything I've read about fish oils is that

they are good for human health in general. You can find a collection

of over 2,000 papers on fish oils here:

http://www.psc-literature.org/fishoil.htm

If I were to pick out some good (and free) review articles, it would

be these:

Calder PC, Grimble RF 2002 Polyunsaturated fatty acids, inflammation

and immunity. Eur. J. Clin. Nutr. 56 Suppl. 3: S14-S19.

http://www.ncbi.nlm.nih.gov/pubmed/12142955

Calder PC 2006 n-3 Polyunsaturated fatty acids, inflammation, and

inflammatory diseases. Am. J. Clin. Nutr. 83: 1505S-1519S.

http://www.ncbi.nlm.nih.gov/pubmed/16841861

Simopoulos AP 2002 Omega-3 fatty acids in inflammation and autoimmune

diseases. J. Am. Coll. Nutr. 21: 495-505.

http://www.ncbi.nlm.nih.gov/pubmed/12480795

Because I am not a doctor of medicine, I can't say that all PSCers

should take fish oils. But I can present some sound information here,

and perhaps this may encourage some members to talk with their

hepatologists about this option.

Best regards,

Dave R.

>

> If I am understanding right, The fish oil or omega 3 or DHA (all

the same thing) fixes the bile duct injury? Or prevents it from

getting worse after the injury?  Looks like PSCers should be taking

fish oil!

> Dave, are you in the medical field.  Just curious.

>  

> Lori A.

>