Alveolar liquid clearance was examined in ventilated, anesthetized guinea pigs. An isosmolar 5% albumin solution was instilled into the lungs. Alveolar liquid clearance was studied over 1 h and was measured from the increase in alveolar protein concentration as water was reabsorbed. Basal alveolar liquid clearance was 38% of instilled volume. The high basal alveolar liquid clearance was not secondary to endogenous catecholamine release. Compared with control animals, epinephrine and the general β-adrenergic agonist isoproterenol increased alveolar liquid clearance to ∼50% of instilled volume ( P < 0.05), whereas the β2-adrenergic agonist terbutaline was without effect. The stimulation of alveolar liquid clearance by epinephrine or isoproterenol was completely inhibited by the addition of the general β-adrenergic inhibitor propranolol or the β1-adrenergic inhibitor atenolol. Alveolar liquid clearance was inhibited by the sodium-channel inhibitor amiloride by 30–40% in control animals and in animals treated with epinephrine or isoproterenol. Isoproterenol and epinephrine, but not terbutaline, increased adenosine 3′,5′-cyclic monophosphate in in vitro incubated lung tissue. The results suggest that alveolar liquid clearance in guinea pigs is mediated partly through amiloride-sensitive sodium channels and that alveolar liquid clearance can be increased by stimulation of primarily β1-adrenergic receptors.

The in vivo effect of 48-h glucocorticoid and thyroid hormone 3,3', 5-triiodine-L-thyronine (T(3)) pretreatment on alveolar epithelial fluid transport was studied in adult rats. An isosmolar 5% albumin solution was instilled, and alveolar fluid clearance was studied for 1 h. Compared with controls, dexamethasone pretreatment increased alveolar fluid clearance by 80%. T(3) pretreatment stimulated alveolar fluid clearance by 65%, and dexamethasone and T(3) had additive effects (132%). Propranolol did not inhibit alveolar fluid clearance in either group, indicating that stimulation was not secondary to endogenous beta-adrenergic stimulation. With the use of bromodeoxyuridine in vivo labeling, there was no evidence of cell proliferation. Alveolar fluid clearance was partially inhibited by amiloride in all groups. Fractional amiloride inhibition was greater in dexamethasone- and dexamethasone-plus-T(3)-pretreated rats than in control animals, but less in T(3)-pretreated rats. In summary, pretreatment with dexamethasone, T(3), or both in combination upregulate in vivo alveolar fluid clearance similarly to short-term beta-adrenergic stimulation. The effects are mediated partly by increased amiloride-sensitive Na(+) transport, because the stimulated alveolar fluid clearance was more amiloride sensitive than in control rats. These observations may have clinical relevance because glucocorticoid therapy is commonly used with acute lung injury.

Background Hormonal ablation is the standard of treatment for advanced androgen-dependent prostate cancer. Although tumor regression is usually achieved at first, the cancer inevitably evolves toward androgen-independence, in part because of the development of mechanisms of resistance and in part because at the tissue level androgen withdrawal is not fully attained. Current research efforts are focused on new therapeutic strategies that will increase the effectiveness of androgen withdrawal and delay recurrence. We used a syngeneic pseudo-orthotropic mouse model of prostate cancer to test the efficacy of combining androgen withdrawal with FDA-approved COX-2 inhibitor celecoxib. Methods GFP-tagged TRAMP-C2 cells were co-implanted with prostate tissue in the dorsal chamber model and tumors were allowed to establish and vascularize. Tumor growth and angiogenesis were monitored in real-time using fluorescent intravital microscopy (IVM). Androgen withdrawal in mice was achieved using surgical castration or chemical hormonal ablation, alone or in combination with celecoxib (15 mg/kg, twice daily). Results Celecoxib alone decreased the growth of prostate tumors mostly by inducing mitotic failure, which resulted in increased apoptosis. Surprisingly, celecoxib did not possess significant angiostatic activity. Surgical or chemical castration prevented the growth of prostate tumors and this, on the other hand, was associated with disruption of the tumor vasculature. Finally, androgen withdrawal combined with celecoxib caused tumor regression through decreased angiogenesis and increased mitosis arrest and apoptosis. Conclusion Celecoxib, a relatively safe COX-2-selective anti-inflammatory drug, significantly increases the efficacy of androgen withdrawal in vivo and warrants further investigation as a complement therapy for advanced prostate cancer.

Androgen deprivation in combination with plumbagin may provide a significant improvement over androgen deprivation alone and deserves further evaluation.