Extreme Resistance to Hypercapnia-Induced Pulmonary Edema of the African Naked Mole-Rat

The African naked-mole rat lives chronically in a hypercapnia due to many individuals living together in small enclosed burrows. At extreme hypercapnia, pulmonary edema is induced in many terrestrial mammals. The present study aim was to examine the resistance naked mole-rats have to the physiological effects of hypercapnia and determine the mechanism of hypercapnia-induced pulmonary edema. We found extreme hypercapnia was unable to induce pulmonary edema in naked mole-rats. Previously, their cutaneous c-fibers were found to be insensitive to acid stimuli and this was thought to be an adaptation to hypercapnia acidosis. Pulmonary c-fibers release the peptide substance P that can induce pulmonary edema. A related peptide, hemokinin-1, has the same endogenous receptor, neurokinin 1, and is also present within the lungs. We predicted that naked mole-rats in response to hypercapnia would have attenuated release of substance P and hemokinin-1 within their lungs. Surprisingly, naked mole-rats had no detectable amount of substance P or hemokinin-1 in lavage fluid at control or after 30% CO2 exposure. We further studied the function of pulmonary c-fiber acid sensitivity in hypercapnia-induced pulmonary edema. Mice that lack channels expressed by c-fibers that are acid sensitive, TrpV1 and ASIC3, were exposed to extreme hypercapnia. We found that the absence of these channels had no effect on hypercapnia-induced pulmonary edema. We also used mice that lacked substance P gene, tac1, expression and found significant increased edema that was counter to our original hypothesis. The volatile anesthetic isoflurane has previously been found to have anti-inflammatory effect on pulmonary induced inflammation. We used isoflurane in conjunction with acute 30% CO2 exposure in mice. We found that isoflurane greatly attenuated hypercapnia-induced edema and abolished the increased release of substance P and hemokinin-1 in lung lavage fluid of wild-type mice. These results indicated that hypercapnia-induced pulmonary edema may not be mediated by the acid-sensitivity of pulmonary c-fibers but may involve hemokinin-1. For the first time, isoflurane was found to attenuate hypercapnia-induced pulmonary edema. The absence of detectable substance P and hemokinin-1 within the naked mole-rat lungs may be part of their adaptation for living in hypercapnia.