Biomedical subjects

David Marsolais

Publications and source records attributed to David Marsolais.

6 recordsLinked to original sources

PubMed2006

Inflammatory cells do not decrease the ultimate tensile strength of intact tendons in vivo and in vitro: protective role of mechanical loading.

Although inflammatory cells and their products are involved in various pathological processes, a possible role in tendon dysfunction has never been convincingly confirmed and extensively investigated. The goal of this study was to determine whether or not an acute inflammatory process deprived of mechanical trauma can induce nonspecific damages to intact collagen fibers. To induce leukocyte accumulation, carrageenan was injected into rat Achilles tendons. We first tested the effect of leukocyte recruitment on the concentrations or activities of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Second, we analyzed at the biochemical, histological, and biomechanical levels the impact of leukocyte invasion on tendons. Finally, collagen bundles isolated from rat-tail tendons were exposed in vitro to mechanical stress and/or inflammatory cells to determine if mechanical loading could protect tendons from the leukocyte proteolytic activity. Carrageenan-induced leukocyte accumulation was associated with an increased matrix metalloproteinase activity and a decreased content of tissue inhibitors of matrix metalloproteinases. However, hydroxyproline content and load to failure did not change significantly in these tendons. Interestingly, mechanical stress, when applied in vitro, protected collagen bundles from inflammatory cell-induced deterioration. Together, our results suggest that acute inflammation does not induce damages to intact and mechanically stressed collagen fibers. This protective effect would not rely on increased tissue inhibitors of matrix metalloproteinases content but would rather be conferred to the intrinsic resistance of mechanically loaded collagen fibers to proteolytic degradation.

Animals↗

PubMed2006

Pifithrin-alpha, an inhibitor of p53 transactivation, alters the inflammatory process and delays tendon healing following acute injury.

Transcription factor p53, which was initially associated with cancer, has now emerged as an important regulator of inflammation and extracellular matrix homeostasis, two processes highly relevant to tendon repair. The goal of this study was to evaluate the effect of a p53 transactivation inhibitor, namely, pifithrin-alpha, on the pathophysiological sequence following collagenase-induced tendon injury. Administration of pifithrin-alpha during the inflammatory phase reduced the accumulation of neutrophils and macrophages by 30 and 40%, respectively, on day 3 postinjury. Pifithrin-alpha failed to reduce the percentage of apoptotic cells following collagenase injection but delayed functional recovery. In uninjured Achilles tendons, pifithrin-alpha increased metalloprotease activity 2.4-fold. Accordingly, pifithrin-alpha reduced the collagen content in intact tendons as well as in injured tendons 7 days posttrauma compared with placebo. The effect of pifithrin-alpha on load to failure and stiffness was also evaluated. The administration of pifithrin-alpha during the inflammatory phase did not significantly decrease the functional deficit 3 days posttrauma. More importantly, load to failure and stiffness were significantly decreased in the pifithrin-alpha group from day 7 to day 28 compared with placebo. Overall, our results suggest that administration of pifithrin-alpha alters the inflammatory process and delays tendon healing. The present findings also support the concept that p53 can regulate extracellular matrix homeostasis in vivo.

Achilles Tendon↗

PubMed2006

Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo.

Sphingosine 1-phosphate (S1P, 1) regulates vascular barrier and lymphoid development, as well as lymphocyte egress from lymphoid organs, by activating high-affinity S1P1 receptors. We used reversible chemical probes (i) to gain mechanistic insights into S1P systems organization not accessible through genetic manipulations and (ii) to investigate their potential for therapeutic modulation. Vascular (but not airway) administration of the preferred R enantiomer of an in vivo-active chiral S1P1 receptor antagonist induced loss of capillary integrity in mouse skin and lung. In contrast, the antagonist did not affect the number of constitutive blood lymphocytes. Instead, alteration of lymphocyte trafficking and phenotype required supraphysiological elevation of S1P1 tone and was reversed by the antagonist. In vivo two-photon imaging of lymph nodes confirmed requirements for obligate agonism, and the data were consistent with the presence of a stromal barrier mechanism for gating lymphocyte egress. Thus, chemical modulation reveals differences in S1P-S1P1 'set points' among tissues and highlights both mechanistic advantages (lymphocyte sequestration) and risks (pulmonary edema) of therapeutic intervention.

Anilides↗

PubMed2005

[Inflammation and tendon healing].

Tendons are extracellular matrix rich structures allowing the transmission of forces generated by skeletal muscles to bones in order to produce movements. Some intrinsic characteristics of tendons, namely hypovascularity and hypocellularity, may explain their slow rate of healing. A growing body of evidence suggests that the inflammatory process, essential for pathogen clearance and injury scavenging, may play opposite functions in tendon healing. For instance, inflammation can lead to degradation of intact collagen and to viable cell death, thereby increasing the functional deficit and recovery period. Paradoxically, many cellular and subcellular events occurring during the inflammatory response lead to the release of a plethora of growth factors that trigger the healing phase. Prostaglandins are implicated in the inflammatory process and may also contribute to the primary steps of tendon healing. Prolonged administration of non steroidal anti-inflammatory drugs (NSAIDs) is a common practice following musculoskeletal injuries. However, there is no clear consensus on the effect of NSAIDs on tendon healing. This review presents a contemporary vision of the inflammatory process following tendon injury and examines the roles of the constitutive and inducible COX-derived prostaglandins. The effect of COX inhibitors will be addressed and special attention will be taken to describe COX-independent effects of these pharmacological inhibitors. Together, this review is an attempt to guide readers toward a more conscientious use of NSAIDs following tendon injuries.

Animals↗

PubMed2003

Macrophages, not neutrophils, infiltrate skeletal muscle in mice deficient in P/E selectins after mechanical reloading.

Our objective was to test the hypothesis that endothelial selectins, P and E selectins, are necessary for leukocyte migration after muscle injury from unloading/reloading. Mice hindlimbs were suspended for 10 days followed by reloading periods of 6 or 24 h after which the soleus muscle was dissected. Light microscopic observations showed that macrophages, but not neutrophils, were able to invade soleus muscles in mice deficient in P/E selectins (P/E-/-) during reloading periods. The recruitment efficiency of neutrophils after 6 and 24 h of reloading was minimal in P/E-/- mice relative to unloaded animals. The recruitment of macrophages in the soleus muscle was preserved in P/E-/- mice. The concentration of macrophages increased by 8.1-fold compared with unloaded muscles in double-mutant mice after 24 h of reloading. The accumulation of macrophages in reloaded muscles did not lead to fiber necrosis. Together, these findings indicate that macrophages can invade skeletal muscle through cellular mechanisms that do not involve P/E selectins during skeletal muscle reloading.

Animals↗

PubMed2003

Nonsteroidal anti-inflammatory drug reduces neutrophil and macrophage accumulation but does not improve tendon regeneration.

Whether nonsteroidal anti-inflammatory drugs have a beneficial effect on tendon regeneration is still a matter of debate. Given that inflammatory cells are thought to induce nonspecific damage following an injury, we tested the hypothesis that a 3-day treatment with diclofenac would protect tendons from inflammatory cell injury and would promote healing. Neutrophil and ED1(+) macrophage concentrations were determined in the paratenon and the core of the rat Achilles tendon following collagenase-induced injury. Hydroxyproline content, edema, and mechanical properties were also evaluated at 1, 3, 7, 14, and 28 days post-trauma. Collagenase injections induced a 70% decrease in the ultimate rupture point at Day 3. Diclofenac treatments (1 mg/kg bid) selectively decreased the accumulation of neutrophils and ED1(+) macrophages by 59% and 35%, respectively, in the paratenon, where blood vessels are numerous, but did not reduce the accumulation of neutrophils and ED1(+) macrophages in the core of the tendon. Edema was significantly reduced on Day 3 but persisted during the remodeling phase in the diclofenac-treated group only. The inhibition of leukocyte accumulation by diclofenac did not translate into a reduction of tissue damage or a promotion of tissue healing, because the mechanical properties of injured Achilles tendons were identical in placebo and diclofenac-treated groups. These results indicate that diclofenac reduced both edema and the accumulation of inflammatory cells within the paratenon but provided no biochemical or functional benefits for the Achilles tendon.

Achilles Tendon↗