Schistosomal Cor pulmonale: A Fluke in the Fas Lane?

Accessible online at: www.karger.com/res The paper by Salama et al. [1, this issue of Respiration] correlating elevated serum Fas levels with cor pulmonale in schistosomiasis (caused by a subgroup of trematodes – flukes) may have broad implications for respiratory physicians. The Fas receptor and Fas ligand (CD95) system, being respectively related to the TNF-receptor (R) and the TNF families, is increasingly being appreciated as having similar complex and temporal relationships to the evolution of acute and chronic disease as do TNF and TNFRs [2–4]. While the focus on Fas/FasL regulation of apoptosis has taken center stage, it is seems likely that as with TNF/TNFR, such a potent system will be found to have multiple immunological regulatory roles [5–7]. Additionally, the evolving understanding of how metalloproteinase ‘sheddases’ such as TACE may either enhance or diminish the inflammatory consequences of TNF and its receptors is now being paralleled by studies of metalloproteinase cleavage of membrane bound FasL (mFasL) [8–12]. The ability of soluble(s) TNF to propagate a lethal inflammatory process if released in large amounts (e.g. meningococcemia), must be appreciated while understanding that membrane bound (m)TNF normally plays the dominant role in the autocrine or paracrine signaling regulating localized acute and chronic disease states [13, 14]. Paradoxically, the shedding of mTNF or mTNFRs may also serve to reduce the degree of host induced injury in response to an infectious agent or injury [2, 15]. It should therefore not be surprising that a similar complex array of events will likely be elucidated within the Fas/FasL system and its interactions with the immune system. It is with this background that Salama et al. [1] showed that increased levels of soluble Fas (sFas) correlated with the severity of the pulmonary hypertension in a population of 15 men with schistosomal cor pulmonale. The serum levels were significantly greater than those found in two control populations: men with cor pulmonale secondary to COPD and aged matched healthy men. While the study has some clear weaknesses, (e.g. no control populations with schistosomiasis without cor pulmonale), it does highlight an emerging body of science suggesting that Fas/ FasL may be critical to understanding one of the most prevalent disease states affecting the human race. It also provides insights into how future understanding of the molecular regulation of apoptosis, inflammation and genetic variability in both host and parasite may be used to prevent morbidity and mortality in schistosomal lung disease, and very likely, lung disease in general [16–20]. The role of apoptosis in defining the evolution of disease is emerging as a fundamental principle in understanding lung inflammatory disease states from sepsis to emphysema [17, 21].