The etiology of liver damage imparts cytokines transforming growth factor beta1 or interleukin-13 as driving forces in fibrogenesis

It is unknown whether transforming growth factor beta1 (TGF-beta1) signaling uniformly participates in fibrogenic chronic liver diseases, irrespective of the underlying origin, or if other cytokines such as interleukin (IL)-13 share in fibrogenesis (e.g., due to regulatory effects on type I pro-collagen expression). TGF-beta1 signaling events were scored in 396 liver tissue samples from patients with diverse chronic liver diseases, including hepatitis B virus (HBV), hepatitis C virus (HCV), Schistosoma japonicum infection, and steatosis/steatohepatitis. Phospho-Smad2 staining correlated significantly with fibrotic stage in patients with HBV infection (n = 112, P < 0.001) and steatosis/steatohepatitis (n = 120, P < 0.01), but not in patients with HCV infection (n = 77, P > 0.05). In tissue with HBx protein expression, phospho-Smad2 was detectable, suggesting a functional link between viral protein expression and TGF-beta1 signaling. For IL-13, immunostaining correlated with fibrotic stage in patients with HCV infection and steatosis/steatohepatitis. IL-13 protein was more abundant in liver tissue lysates from three HCV patients compared with controls, as were IL-13 serum levels in 68 patients with chronic HCV infection compared with 20 healthy volunteers (72.87 +/- 26.38 versus 45.41 +/- 3.73, P < 0.001). Immunohistochemistry results suggest that IL-13-mediated liver fibrogenesis may take place in the absence of phospho-signal transducer and activator of transcription protein 6 signaling. In a subgroup of patients with advanced liver fibrosis (stage > or =3), neither TGF-beta nor IL-13 signaling was detectable. Conclusion: Depending on the cause of liver damage, a predominance of TGF-beta or IL-13 signaling is found. TGF-beta1 predominance is detected in HBV-related liver fibrogenesis and IL-13 predominance in chronic HCV infection. In some instances, the underlying fibrogenic mediator remains enigmatic.

Breakdown of chlorophyll: A nonenzymatic reaction accounts for the formation of the colorless "nonfluorescent" chlorophyll catabolites

Senescent higher plants degrade their chlorophylls (Chls) to polar colorless tetrapyrrolic Chl catabolites, which accumulate in the vacuoles. In extracts from degreened leaves of the tree Cercidiphyllum japonicum an unpolar catabolite of this type was discovered. This tetrapyrrole was named Cj-NCC-2 and was found to be identical with the product of a stereoselective nonenzymatic isomerization of a “fluorescent” Chl catabolite. This (bio-mimetic) formation of the “nonfluorescent” catabolite Cj-NCC-2 took place readily at ambient temperature and at pH 4.9 in aqueous solution. The indicated nonenzymatic process is able to account for a crucial step during Chl breakdown in senescent higher plants. Once delivered to the acidic vacuoles, the fluorescent Chl catabolites are due to undergo a rapid, stereoselective isomerization to the ubiquitous nonfluorescent catabolites. The degradation of the Chl macrocycle is thus indicated to rely on just two known enzymes, one of which is senescence specific and cuts open the chlorin macroring. The two enzymes supply the fluorescent Chl catabolites, which are “programmed” to isomerize further rapidly in an acidic medium, as shown here. Indeed, only small amounts of the latter are temporarily observable during senescence in higher plants.