Collagen, the major structural component of nearly all mammalian tissues, undergoes extensive proteolytic remodeling during developmental states and a variety of life-threatening diseases such as cancer, myocardial infarction, and fibrosis. While degraded collagen could be an important marker of tissue damage, it is difficult to detect and target using conventional tools. Here, we show that a designed peptide (collagen hybridizing peptide: CHP), which specifically hybridizes to the degraded, unfolded collagen chains, can be used to image degraded collagen and inform tissue remodeling activity in various tissues: labeled with 5-carboxyfluorescein and biotin, CHPs enabled direct localization and quantification of collagen degradation in isolated tissues within pathologic states ranging from osteoarthritis and myocardial infarction to glomerulonephritis and pulmonary fibrosis, as well as in normal tissues during developmental programs associated with embryonic bone formation and skin aging. The results indicate the general correlation between the level of collagen remodeling and the amount of denatured collagen in tissue and show that the CHP probes can be used across species and collagen types, providing a versatile tool for not only pathology and developmental biology research but also histology-based disease diagnosis, staging, and therapeutic screening. This study lays the foundation for further testing CHP as a targeting moiety for theranostic delivery in various animal models.

Rationale-IL-9 is a pleiotropic cytokine that has multiple effects on structural as well as numerous hematopoietic cells, which are central to the pathogenesis of asthma.Objectives-The contribution of IL-9 to asthma pathogenesis has thus far been unclear, due to conflicting reports in the literature. These earlier studies focused on the role of IL-9 in acute inflammatory models; here we have investigated the effects of IL-9 blockade during chronic allergic inflammation.Methods-Mice were exposed to either prolonged ovalbumin or house dust mite allergen challenge to induce chronic inflammation and airway remodeling.

A characteristic feature of rheumatoid arthritis is the abundance of inflammatory cells in the diseased joint. Two major components of this infiltrate are neutrophils in the synovial fluid and macrophages in the synovial tissue. These cells produce cytokines including tumor necrosis factor α and other proinflammatory mediators that likely drive the disease through its effector phases. To investigate what mechanisms underlie the recruitment of these cells into the synovial fluid and tissue, we performed expression analyses of chemoattractant receptors in a related family that includes the anaphylatoxin receptors and the formyl-MetLeuPhe receptor. We then examined the effect of targeted disruption of two abundantly expressed chemoattractant receptors, the receptors for C3a and C5a, on arthritogenesis in a mouse model of disease. We report that genetic ablation of C5a receptor expression completely protects mice from arthritis.

Systemic sclerosis (SSc) is a debilitating inflammatory and fibrotic disease that affects the skin and internal organs. Although the pathophysiology of SSc remains poorly characterized, mononuclear cells, mainly macrophages and T cells, have been implicated in inflammation and fibrosis. Inducible costimulator (ICOS), which is expressed on a subset of memory T helper (T) and T follicular helper (T) cells, has been shown to be increased in SSc and associated with disease pathology. However, the identity of the relevant ICOS T cells and their contribution to inflammation and fibrosis in SSc are still unknown. We show that CD4 ICOS-expressing T cells with a T-like phenotype infiltrate the skin of patients with SSc and are correlated with dermal fibrosis and clinical disease status. ICOS T-like cells were found to be increased in the skin of graft-versus-host disease (GVHD)-SSc mice and contributed to dermal fibrosis via an interleukin-21- and matrix metalloproteinase 12-dependent mechanism. Administration of an anti-ICOS antibody to GVHD-SSc mice prevented the expansion of ICOS T-like cells and inhibited inflammation and dermal fibrosis. Interleukin-21 neutralization in GVHD-SSc mice blocked disease pathogenesis by reducing skin fibrosis. These results identify ICOS T-like profibrotic cells as key drivers of fibrosis in a GVHD-SSc model and suggest that inhibition of these cells could offer therapeutic benefit for SSc.

Summary:Purpose: The epileptic EL mouse has been studied extensively as a model of multifactorial epilepsy. Although EL mice have a seizure occasionally during routine handling associated with cage changing, most studies have used vigorous tossing or shaking procedures for seizure induction. A new seizure testing procedure was developed that involved gentle handling and simulated situations associated with emotional stress in rodents. This new testing procedure was used to identify and characterize several environmental risk factors that influence seizure predisposition in EL mice.Methods: Ten adult EL mice were monitored for 7 days under 24-h light/dark video surveillance to assess the frequency of spontaneous seizures. The development of handling-induced seizures also was studied in EL mice, in nonepileptic ABP and DDY mice, and in reciprocal ABP x EL F, hybrids from ages 30-1 80 days.Results; Seizure induction was necessary in EL mice, as spontaneous clinical seizures were not observed. Handlinginduced seizure susceptibility was strongly age and gender dependent in naive EL mice (not previously handled) and peaked -90 days, with males significantly more susceptible than females. No seizures were induced by handling in the nonepileptic mouse strains (ABP and DDY) over the testing period. Handling and seizures at young ages in EL and EL x ABP F, hybrid mice significantly enhanced their seizure susceptibility when they were tested again 1 month later. A significant "Gowers effect" was seen also in EL mice. Furthermore, susceptibility was higher in ABP x EL F, hybrids than in their reciprocal EL x ABP F, hybrids at 90-150 days.Conclusions: Seizure susceptibility in EL mice was significantly influenced by a number of environmental factors including age, gender, maternal/paternal effects, prior handling, and seizure history. The emotional stresdfear response is the likely trigger for seizure induction in EL mice. An early life experience stress-diathesis model, similar to that proposed for major depression in humans, was applicable to the development of seizure susceptibility in EL mice. The new seizure test will be useful for defining gene+nvironment interactions and in identifying susceptibility genes for multifactorial epilepsy.