Submitted on July 26, 2004
Accepted on September 24, 2004
Bone marrow-derived cells contribute to contractile dysfunction in endotoxic shock
Brian W. Binck1, May F. Tsen1, Miguel Islas2, Jean White3, Roger A. Schultz4, Monte S. Willis1, J. Victor Garcia2, Jureta W. Horton3, and James A. Thomas1*
1 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA
2 Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
3 Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA
4 Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
* To whom correspondence should be addressed. E-mail: James.Thomas{at}utsouthwestern.edu.
How infection precipitates depressed contractility is incompletely understood, but may involve the immune, nervous, and endocrine systems as well as the heart itself. In this study, we examined the role of TLR4 in LPS-induced myocardial contractile depression. Eighteen hours following endotoxin challenge, we compared contractile
responses in hearts from wild type and TLR4-deficient mice using modified Langendorff preparations. Unlike hearts from WT mice, TLR4-deficient hearts did not reveal
significant contractile dysfunction following LPS administration, as measured by decreased responses in LVPmax, +dP/dtmax, and -dP/dtmax in ex-vivo Langendorff
preparations. These findings indicate a requirement for TLR4 in LPS-induced contractile depression. To determine the contribution of bone marrow-derived TLR4 function to
LPS-induced myocardial dysfunction, we generated TLR4 chimeras using adoptive transfer between histocompatible mouse strains: either TLR4-deficient mice with TLR4
+/+ bone marrow-derived cells or TLR4 +/+ animals lacking TLR4 in their hematopoietic cells. We then compared the contractile responses of engrafted animals after LPS
challenges. Engraftment of TLR4-deficient mice with WT marrow restored sensitivity to the myocardial depressant effects of LPS in TLR4-deficient hearts (p<0.05). Inactivation of bone marrow-derived TLR4 function, via transplantation of WT mice with TLR4-/-
marrow, however, did not protect against the depressant effect of endotoxin. These findings indicate that bone marrow-derived TLR4 activity is sufficient to confer
sensitivity to mice lacking TLR4 in all other tissues. However, because inactivation of marrow-derived TLR4 function alone does not protect against endotoxin-triggered
3 contractile dysfunction, TLR4 function in other tissues may also contribute to this response.
