Publications

Hepatic stellate cells are widely recognized for their contribution to liver fibrosis. This study investigated whether these cells also promote hepatic inflammation by producing neutrophil chemoattractants. Specifically, stellate cells were examined as potential sources of cytokine-induced neutrophil chemoattractant (CINC), a rat chemokine resembling human interleukin-8. Stellate cells from normal rat liver expressed little or no CINC. In culture, CINC mRNA was induced rapidly, coinciding with the phenomenon of culture activation. CINC mRNA rose 4.6-fold within 3 days and was accompanied by secretion of immunoreactive and biologically active CINC protein (4.1 ng . microgram DNA-1 . day-1). Studies in vivo demonstrated that CINC could be induced in stellate cells during liver injury. CINC mRNA rose significantly (4- to 6-fold) in two models of liver disease, both of which cause stellate cell activation. In summary, the data indicate that CINC is induced during stellate cell activation in culture and in vivo. They suggest that stellate cell-derived CINC can promote hepatic inflammation in vivo.

Coronary artery disease kills more women than all cancers combined, yet the clinical picture in women is different enough from men that the diagnosis can be missed or delayed. A cardiologist highlights these gender-based differences and explains why certain diagnostic tests are better than others at identifying CAD in women. Coronary artery disease (CAD) is the leading killer of women in the US. After menopause, mortality rates from CAD in women nearly equal those of men. Yet the clinical picture in women is different enough from that in men that it can obscure the correct diagnosis. Women are 10 years older than men, on average, when presenting with CAD, possibly due to delayed diagnosis or presentation. Differences in symptomatology between men and women are important to note. For example, other diseases, such as arthritis or osteoporosis, can obscure CAD symptoms. Further, compared with men, women's chest pain is more often associated with abdominal pain, dyspnea, nausea, and fatigue. More women than men with CAD have diabetes, hypertension, hypercholesterolemia, and a family history of CAD. Clinicians need to know how to assess the gender-specific pretest likelihood of CAD in women, starting with a careful review of the patient's chest pain history. Other risk factors, including smoking, abdominal obesity, and certain comorbidities, should be taken into consideration. The diagnostic accuracy of exercise testing is slightly lower for women than men. Certain diagnostic tests, particularly exercise echocardiography and exercise thallium/sestamibi testing, offer more prognostic information than traditional exercise electrocardiographic studies without imaging. Mortality associated with interventional procedures--such as angioplasty and coronary artery bypass grafting (CABG)--is slightly higher in women, although long-term survival rates are similar for both sexes. Detection of CAD at an earlier stage in women may result in earlier referrals for CABG, with the benefit of lower associated mortality rates.

Inactivation of the integrin beta6 subunit gene in mice resulted in an unexpected phenotype-functionally significant inflammation of the skin and lungs. These findings suggested a role for ligation of the alphav beta6 integrin on epithelial cells in downregulating epithelial inflammation. However, the results of gene inactivation could have been due to inactivation of adjacent genes and provided no information about the role of this integrin in specific populations of epithelial cells. In the current study, we used transgenic mice constitutively expressing the human beta6 subunit in alveolar type II cells and bronchiolar epithelial cells to examine directly the significance of alphav beta6 in these cells. Expression of this transgene largely inhibited the increases in airspace lymphocytes and macrophages and the lymphocyte and macrophage activation caused by inactivation of the beta6 subunit gene, and reduced the peribronchial and perivascular accumulations of lymphocytes. In the genetically mixed mice used for this study, we identified airway eosinophilia as an additional effect of beta6 inactivation. This effect was also partially inhibited by limited expression of the human transgene. These results definitively identify a role for distal lung epithelial alphav beta6 in downregulating pulmonary inflammation and suggest that interventions augmenting beta6 expression or function in these cells could influence the course of inflammatory lung diseases.