Written by Ester Fride
“Pulmonary dysfunction has long been considered the primary cause for morbidity and mortality in CF (Pilewski and Frizell 1999), with malnutrition appearing as a compounding detrimental factor (Borowitz 1996). More recently however, malnutrition is being recognized as playing a primary role in disease progression (Borowitz
1996; Schoni and Casaulta-Aebischer 2000) possibly even being responsible for lung pathology and infections (Yu et al., 2000).
Fatty Acid Balance
A fatty acid imbalance is observed in CF patients, including elevated levels of arachidonic acid and reduced levels of DHA. (…) the low DHA levels have been shown to play a fundamental role in the pathogenesis in the organs affected by the CF disease: lungs, pancreas and ileum (Freedman et al. 1999).
Thus, further decreasing DHA levels in cftr-/- mice worsened pathological manifestations, while elevating DHA levels by oral supplementation corrected the lipid imbalance and reversed the pathology of the affected organs.
Is it possible that the synthesis of endocannabinoids, being fatty acid derivatives, is also modulated by CFTR proteins? There are a number of striking parallels between the clinical manifestations of CF and the domains of cannabinoid and endocannabinoid influence, including lack of appetite, nausea, diarrhea, and lung disease. Low endocannabinoid levels could explain the appearance of these symptoms. However, even in the absence of a causative role, it is proposed here that by stimulating the cannabinoid system, some of the CF pathology symptoms may be alleviated.
Vomiting induced by coughing (Blecker et al. 2000) often exacerbates the development of malnutrition in cystic fibrosis. Antiemetic benefits of THC have been demonstrated in its effective relief of chemotherapy-induced nausea and vomiting (Mechoulam et al., 1998b; Abrahamov et al. 1995). Therefore the antiemetic potential of cannabinoids would be expected to contribute to appetite enhancement induced by cannabinoids in CF patients.
Diarrhea appears in CF as a result of inadequate digestion due to pancreatic insufficiency (Rolles 1998). Cannabinoids inhibit intestinal motility via local CB1 (Colombo et al. 1998; Tyler et al. 2000) and/or via CB2 (Fride 1995; Hanus et al. 1999) receptors. Therefore administration of cannabinoids to CF patients may counteract diarrhea and thereby help prevent loss of nutrients.
Most destruction of lung tissue in CF is now thought to be secondary to a very aggressive neutrophilic inflammatory response (Konstan & Berger 1997; Wagener et al. 1997). This ultimately leads to respiratory failure. The antiinflammatory potential of cannabinoids is well documented (Klein et al. 2000; Straus 2001) and is thought to occur by interference with the arachidonic acid-eicosanoid synthetic pathways (McPartland 2001). We have demonstrated in a mouse model of arachidonic acid-induced ear inflammation that cannabinoids and endocannabinoids are effective antiinflammatory agents acting via CB receptors (Hanus et al. 1999; Fride et al. unpublished observations).
Since cannabinoid receptors are present in lungs (Calignano et al. 2000), THC may be of additional benefit for CF patients, by reducing inflammatory processes in the lungs.
It has been demonstrated recently that bronchodilating and cough-reducing activity of endocannabinoids in irritated lungs are mediated by local CB1 receptors (Calignano et al. 2000). Therefore cannabinoids may also benefit CF patients by their bronchodilating and cough suppressing effects.
CF patients suffer pain from a variety of sources (Ravilly et al. 1996) including abdominal pain related to steatorrhea and malabsorption (Zeltzer et al. 1996), chest pain due to impacted sputum, pleuritic involvement with lung inflammation and infection, or chest wall pain associated with developing kyphoscoliosis and decreased chest wall mobility (Massie et al. 1998). Pain may also occur from gall bladder or kidney stones or from osteoporosis (Haworth et al. 1999; Lambert 2000; Ravilly et al. 1996). Cannabinoids are analgesics effective in a variety of conditions (Mechoulam et al. 1998b; Martin and Lichtman 1998), acting via cannabinoid receptors within as well as outside the brain and spinal cord and suppressing both acute and chronic pain (Pertwee 2001).
In this paper a novel therapeutic target for cannabis is proposed, based on recent developments in research on cannabis on one hand, and on research on cystic fibrosis on the other. Recent findings suggest that the primary factors in the pathogenesis of CF includes fatty acid imbalance, possibly leading to such major manifestations of CF as chronic inflammation of the lungs and pancreatic disease (Greener 2000; Freedman et al. 1999). In the final stages of the disease malnutrition accompanied by a lack of appetite is frequently seen (Anthony et al. 1999; Schoni and Casaulta-Aebischer 2000). Additional symptoms of the disease may include pain due to a variety of sources (Ravilly et al. 1996), diarrhea (Rolles 1998) and nausea (Blecker et al. 2000).
Intriguingly, the therapeutic effects of cannabinoids include the potential to counteract each of these conditions. Thus appetite enhancement (Beal et al. 1997) and a critical role in food ingestion (Fride et al. 2001), analgesic, antiemetic, antiinflammatory, inhibition of intestinal motility and bronchodilating effects have been demonstrated (Calignano et al. 2001; Colombo et al. 1998; Fride 1995; Mechoulam et al. 1998b; Hanus et al. 1999; Tyler et al. 2000).
It is proposed here, that CFTR not only regulates fatty acid balance but also endocannabinoid biosynthesis. Such mechanism predicts that low levels of endocannabioids in CF patients and in cftr-/- mice will be found, which could be responsible for many symptoms. It is hoped that affirmative data will eventually lead to the use of cannabinoids at more initial stages of cystic fibrosis (Figure 2).”