25 research outputs found
Leukocyte recruitment and control of vascular permeability in acute inflammation
The inflammatory process is fundamental in host defense against tissue
injury or infection. However, the inflammatory reaction may itself cause
harm to the host and contribute to tissue damage and organ dysfunction.
Leukocyte recruitment and edema formation are key components of the
inflammatory response. This thesis reports experiments that were
undertaken to further elucidate the mechanisms controlling leukocyte
extravasation and concurrent alteration of vascular permeability in acute
inflammation.
In order for leukocytes to penetrate the vessel wall they need to
sequentially interact with the endothelial lining and the perivascular
basement membrane (BM) of which laminin-411 is a major constituent. The
role of BM laminin-411 in leukocyte recruitment to inflammatory loci was
addressed using Ξ±4 chain deficient (Lam4-/-) and wild-type (WT) mice.
Recruitment of all major leukocyte subsets (neutrophils, monocytes, and
lymphocytes) was reduced in Lam4-/- mice compared to WT. With the use of
intravital microscopy it was concluded that this decrease was due to
impaired diapedesis through the vessel wall.
Concurrent with neutrophil recruitment to extravascular tissue, there is
an increase in vascular permeability. However, the mechanism behind this
alteration is unknown. It was shown that stimulation of neutrophils with
the potent chemoattractant leukotriene B4 (LTB4) leads to degranulation
and release of, amongst others, heparin binding protein (HBP). Further,
postsecretory supernatants from LTB4-stimulated neutrophils induced
intracellular calcium mobilization in endothelial cells in vitro and
increase in vascular permeability in vivo. Selective removal of HBP from
the supernatant significantly reduced these activities indicating a role
for HBP in LTB4-induced plasma extravasation. The mechanism behind
neutrophil-induced alteration of endothelial barrier function was further
investigated and revealed a pivotal role of the kallikrein-kinin system.
Neutrophil activation was shown to enable proteolytic processing of high
molecular weight kininogen bound to endothelial cells. Accordingly,
plasma exudation in vivo in response to challenge with leukocyte
chemoattractants was largely annulled by antagonists of the
kallikrein-kinin system. Collectively, the data provide novel insight
into the regulation of neutrophil-induced plasma extravasation and may
help to identify better therapeutic strategies for interventions in
inflammatory disease.
To investigate the role of neutrophil-induced alterations in vascular
permeability in a clinically relevant setting, experiments were performed
using controlled cortical impact (CCI) as a model for traumatic brain
injury (TBI) in normal mice and in mice that were depleted of
neutrophils. Neutrophil depletion did not significantly affect plasma
leakage across the bloodbrain barrier after CCI. Yet, neutrophils were
found to play a role in edema formation in brain tissue after injury. At
a later phase, neutropenic mice displayed a decreased number of activated
microglia, and an attenuation of tissue loss after injury. These results
suggest that neutrophils contribute to the secondary injury following
TBI. Altogether, this thesis provides insight into the role of the BM in
leukocyte recruitment and clarifies the mechanism behind
neutrophil-induced edema formation in acute inflammation
ΠΠ°ΡΠΊΠ΅ΡΡ Π²ΠΎΡΠΏΠ°Π»Π΅Π½ΠΈΡ ΠΏΡΠΈ Π°ΡΠ΅ΡΠΎΡΠΊΠ»Π΅ΡΠΎΡΠΈΡΠ΅ΡΠΊΠΈΡ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΡΡ ΡΠΎΡΡΠ΄ΠΈΡΡΠΎΠΉ ΡΡΠ΅Π½ΠΊΠΈ Ρ ΠΏΠ°ΡΠΈΠ΅Π½ΡΠΎΠ² Ρ ΠΈΡΠ΅ΠΌΠΈΡΠ΅ΡΠΊΠΎΠΉ Π±ΠΎΠ»Π΅Π·Π½ΡΡ ΡΠ΅ΡΠ΄ΡΠ°
ΠΈΡΠ΅ΠΌΠΈΡΠ΅ΡΠΊΠ°Ρ Π±ΠΎΠ»Π΅Π·Π½Ρ ΡΠ΅ΡΠ΄ΡΠ°Π°ΡΠ΅ΡΠΎΡΠΊΠ»Π΅ΡΠΎΠ·ΡΠΈΡΠΎΠΊΠΈΠ½
ΠΠΊΡΠΈΠ²Π½ΠΎΡΡΡ ΠΌΠΈΠΊΡΠΎΡΠ»ΠΎΡΡ ΠΊΠ°ΠΊ ΠΏΠΎΠΊΠ°Π·Π°ΡΠ΅Π»Ρ ΡΠΎΠΊΡΠΈΡΠ½ΠΎΡΡΠΈ ΠΌΠΎΡΡΠΊΠΈΡ Π΄ΠΎΠ½Π½ΡΡ ΠΎΡΠ»ΠΎΠΆΠ΅Π½ΠΈΠΉ ΡΠ΅Π»ΡΡΠΎΠ²ΠΎΠΉ Π·ΠΎΠ½Ρ Π§Π΅ΡΠ½ΠΎΠ³ΠΎ ΠΌΠΎΡΡ ΠΈ ΠΠ΅ΡΡΠ΅Π½ΡΠΊΠΎΠ³ΠΎ ΠΏΡΠΎΠ»ΠΈΠ²Π°
ΠΠ·ΡΡΠ΅Π½Π° ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π»ΡΠ½Π°Ρ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΡ Π΄ΠΎΠ½Π½ΠΎΠΉ ΠΌΠΈΠΊΡΠΎΡΠ»ΠΎΡΡ Π² ΠΌΠ΅ΡΡΠ°Ρ
ΡΡΠ΅ΡΠΊΠΈ ΠΎΡΡΠ°ΡΠΊΠΎΠ² Ρ
ΠΈΠΌΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠΎΠΊΡΠΈΠΊΠ°Π½ΡΠΎΠ², Π·Π°ΡΠΎΠΏΠ»Π΅Π½Π½ΡΡ
Π² ΠΏΠ΅ΡΠΈΠΎΠ΄ ΠΡΠΎΡΠΎΠΉ ΠΠΈΡΠΎΠ²ΠΎΠΉ Π²ΠΎΠΉΠ½Ρ Π₯Π₯ Π². ΠΡΠΌΠ΅ΡΠ΅Π½Ρ ΠΎΡΠΎΠ±Π΅Π½Π½ΠΎΡΡΠΈ Π²ΠΎΡΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½ΠΈΡ ΠΆΠΈΠ·Π½Π΅Π΄Π΅ΡΡΠ΅Π»ΡΠ½ΠΎΡΡΠΈ ΠΌΠΈΠΊΡΠΎΡΠ»ΠΎΡΡ ΠΏΡΠΈ ΡΠ°Π·Π»ΠΈΡΠ½ΡΡ
ΡΡΠΎΠ²Π½ΡΡ
Π·Π°Π³ΡΡΠ·Π½Π΅Π½ΠΈΡ Π΄ΠΎΠ½Π½ΡΡ
ΠΎΡΠ»ΠΎΠΆΠ΅Π½ΠΈΠΉ ΠΌΡΡΡΡΠΊΠΎΠΌ ΠΈ Ρ
Π»ΠΎΡΠΈΡΠΎΠ²Π°Π½Π½ΡΠΌΠΈ ΠΎΡΠ³Π°Π½ΠΈΡΠ΅ΡΠΊΠΈΠΌΠΈ ΡΡΠ»ΡΡΠΈΠ΄Π°ΠΌΠΈ. ΠΠΎΠ»ΡΡΠ΅Π½Π½ΡΠ΅ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΡ ΠΏΠ΅ΡΡΠΏΠ΅ΠΊΡΠΈΠ²Π½ΠΎ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°ΡΡ ΠΏΡΠΈ ΠΎΡΠ΅Π½ΠΊΠ΅ ΡΠΊΠΎΠ»ΠΎΠ³ΠΈΡΠ΅ΡΠΊΠΎΠ³ΠΎ ΡΠΎΡΡΠΎΡΠ½ΠΈΡ Π΄ΠΎΠ½Π½ΡΡ
ΠΎΡΠ»ΠΎΠΆΠ΅Π½ΠΈΠΉ Π² Π·Π°Π³ΡΡΠ·Π½Π΅Π½Π½ΡΡ
ΠΏΡΠΈΠ±ΡΠ΅ΠΆΠ½ΡΡ
Π°ΠΊΠ²Π°ΡΠΎΡΠΈΡΡ
Neutrophil depletion reduces edema formation and tissue loss following traumatic brain injury in mice
Background: Brain edema as a result of secondary injury following traumatic brain injury (TBI) is a major clinical concern. Neutrophils are known to cause increased vascular permeability leading to edema formation in peripheral tissue, but their role in the pathology following TBI remains unclear. Methods: In this study we used controlled cortical impact (CCI) as a model for TBI and investigated the role of neutrophils in the response to injury. The outcome of mice that were depleted of neutrophils using an anti-Gr-1 antibody was compared to that in mice with intact neutrophil count. The effect of neutrophil depletion on blood-brain barrier function was assessed by Evan's blue dye extravasation, and analysis of brain water content was used as a measurement of brain edema formation (24 and 48 hours after CCI). Lesion volume was measured 7 and 14 days after CCI. Immunohistochemistry was used to assess cell death, using a marker for cleaved caspase-3 at 24 hours after injury, and microglial/macrophage activation 7 days after CCI. Data were analyzed using Mann-Whitney test for non-parametric data. Results: Neutrophil depletion did not significantly affect Evan's blue extravasation at any time-point after CCI. However, neutrophil-depleted mice exhibited a decreased water content both at 24 and 48 hours after CCI indicating reduced edema formation. Furthermore, brain tissue loss was attenuated in neutropenic mice at 7 and 14 days after injury. Additionally, these mice had a significantly reduced number of activated microglia/macrophages 7 days after CCI, and of cleaved caspase-3 positive cells 24 h after injury. Conclusion: Our results suggest that neutrophils are involved in the edema formation, but not the extravasation of large proteins, as well as contributing to cell death and tissue loss following TBI in mice
Muscle Weakness in Rheumatoid Arthritis: The Role of Ca2+ and Free Radical Signaling
In addition to the primary symptoms arising from inflammatory processes in the joints, muscle weakness is commonly reported by patients with rheumatoid arthritis (RA). Muscle weakness not only reduces the quality of life for the affected patients, but also dramatically increases the burden on society since patients' work ability decreases. A 25β70% reduction in muscular strength has been observed in pateints with RA when compared with age-matched healthy controls. The reduction in muscle strength is often larger than what could be explained by the reduction in muscle size in patients with RA, which indicates that intracellular (intrinsic) muscle dysfunction plays an important role in the underlying mechanism of muscle weakness associated with RA. In this review, we highlight the present understanding of RA-associated muscle weakness with special focus on how enhanced Ca2+ release from the ryanodine receptor and free radicals (reactive oxygen/nitrogen species) contributes to muscle weakness, and recent developments of novel therapeutic interventions
Peer Teaching in Undergraduate Medical Education: What are the Learning Outputs for the Student-Teachers? A Systematic Review
Introduction: To achieve quality in medical education, peer teaching, understood as students taking on roles as educators for peers, is frequently used as a teaching intervention. While the benefits of peer teaching for learners and faculty are described in detail in the literature, less attention is given to the learning outputs for the student-teachers. This systematic review focuses on the learning outputs for medical undergraduates acting as student-teachers in the last decade (2012β 2022).
Aim: Our aim is to describe what learning outputs student-teachers have from peer teaching, and map what research methods are used to assess the outputs. We defined learning outputs in a broad sense, including all types of learning experiences, intended and non-intended, associated with being a peer teacher.
Methods: A literature search was conducted in four electronic databases. Title, abstract and full text were screened by 8 independent reviewers and selection was based on predefined eligibility criteria. We excluded papers not describing structured peer teaching interventions with student-teachers in a formalized role. From the included articles we extracted information about the learning outputs of being a student-teacher as medical undergraduate.
Results: From 668 potential titles, 100 were obtained as full-texts, and 45 selected after close examination, group deliberation, updated search and quality assessment using MERSQI score (average score 10/18). Most articles reported learning outputs using mixed methods (67%). Student-teachers reported an increase in subject-specific learning (62%), pedagogical knowledge and skills (49%), personal outputs (31%) and generic skills (38%). Most articles reported outputs using self-reported data (91%).
Conclusion: Although there are few studies that systematically investigate student-teachers learning outputs, evidence suggests that peer teaching offers learning outputs for the student-teachers and helps them become better physicians. Further research is needed to enhance learning outputs for student-teachers and systematically investigate student-teachersβ learning outputs and its impact on student-teachers.publishedVersio
Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation
Neutrophil recruitment and plasma exudation are key elements in the immune response to injury or infection. Activated neutrophils stimulate opening of the endothelial barrier; however, the underlying mechanisms have remained largely unknown. In this study, we identified a pivotal role of the proinflammatory kallikrein-kinin system and consequent formation of bradykinin in neutrophil-evoked vascular leak. In mouse and hamster models of acute inflammation, inhibitors of bradykinin generation, and signaling markedly reduced plasma exudation in response to chemoattractant activation of neutrophils. The neutrophil-driven leak was likewise suppressed in mice deficient in either the bradykinin B2 receptor or factor XII (initiator of the kallikrein-kinin system). In human endothelial cell monolayers, material secreted from activated neutrophils induced cytoskeletal rearrangement, leading to paracellular gap formation in a bradykinin-dependent manner. As a mechanistic basis, we found that a neutrophil-derived heparin-binding protein (HBP/azurocidin) displaced the bradykinin precursor high-molecular-weight kininogen from endothelial cells, thereby enabling proteolytic processing of kininogen into bradykinin by neutrophil and plasma proteases. These data provide novel insight into the signaling pathway by which neutrophils open up the endothelial barrier and identify the kallikrein-kinin system as a target for therapeutic interventions in acute inflammatory reactions.-Kenne, E., Rasmuson, J., RennΓ©, T., Vieira, M. L., MΓΌller-Esterl, W., Herwald, H., Lindbom, L. Neutrophils engage the kallikrein-kinin system to open up the endothelial barrier in acute inflammation