Repeated lung injury due to alpha-naphthylthiourea causes right ventricular hypertrophy in rats

Abstract

Acute lung injury due to alpha-naphthylthiourea (ANTU) is associated with increased permeability edema, transient pulmonary hypertension, and increased vascular reactivity. We sought to determine whether repeated administration of ANTU caused right ventricular hypertrophy. Rats were injected weekly for 4 wk with ANTU or an equivalent volume of the vehicle Tween 80. Rats injected repeatedly with ANTU in doses of 5-10 mg/kg body wt had increased ratios of right ventricular to left ventricular plus septal weights. The right ventricular hypertrophy in ANTU-treated rats was associated with right ventricular systolic hypertension. Repeated injections of ANTU also caused transient pulmonary edema after each dose, as evidenced by increased wet-to-dry lung weight ratios after 4 h, which returned to normal by 24 h. Lungs isolated from ANTU-injected rats had greater pressor responses to hypoxia and to angiotensin II than lungs from Tween 80-injected rats. Pressure-flow curves of isolated lungs, arterial blood gases, and hematocrits were similar in rats treated repetitively with ANTU or Tween alone. Lung histology was also similar in ANTU and control lungs, as were measurements of arterial medial thickness and ratios of numbers of arteries/100 alveoli, indicating that substantial vascular remodeling had not occurred. Thus, four weekly ANTU injections in rats caused right ventricular hypertrophy, probably due to pulmonary hypertension. We speculate that the pulmonary hypertension was due, at least in part, to sustained vasoconstriction, which somehow resulted from repeated acute lung injury.

Adenosine protected against pulmonary edema through transporter- and receptor A2-mediated endothelial barrier enhancement

“…The role of increased adenosine in protection against vascular permeability has also been suggested by demonstrations that adenosine deaminase inhibitor, deoxycoformycin (Pentostatin), which is presumed to elevate adenosine levels, attenuated microvascular dysfunction and improved survival in sepsis (13). In the current study, we demonstrated that administration of Pentostatin, either before or after ALI, significantly attenuated the degree of edema in lungs of animals exposed to ANTU, which causes a non-inflammatory ALI (30,31). In previous studies of deoxycoformycin attenuation of hypoxiainduced lung edema (13,20), lung adenosine levels were not measured.…”

“…Thus, it is possible that increased adenosine prevents inflammation and thus edema formation, but is ineffective in reversing inflammation and subsequent edema formation. ANTU causes pulmonary edema and ALI without accumulation of inflammatory cells in lung (30,31). Thus, the ANTU-induced non-inflammatory model of ALI allowed us to demonstrate that adenosine attenuates pulmonary edema through modulation of vascular endothelial permeability, rather than via effects on the inflammatory response.…”

“…For histological assessment of pulmonary edema, the lungs were inflation fixed under constant pressure of 20 cmH 2O with 4% paraformaldehyde and immersed in paraformaldehyde for 24 h, as we previously described (30). The lungs were subsequently fixed, and 1 m sagittal sections were stained with a 1% hematoxylin and eosin solution.…”

“…Since Pentostatin enhanced pulmonary endothelial basal barrier function in vitro, we next tested its effects on lung edema using a rodent model of ALI. We have previously shown that ANTU causes pulmonary edema and ALI without the accumulation of inflammatory cells in lung (30,31,47). Adenosine has been reported to be protective against lung injury through A 1 and A 2A receptor-mediated anti-inflammatory actions (39,52,56).…”

“…We further demonstrated that elevation of adenosine by inhibition of adenosine deaminase with Pentostatin significantly enhanced endothelial basal barrier function, an effect that was also associated with enhanced Rac1 activation and with increased focal adhesion complexes and adherens junctions. Finally, using a non-inflammatory ALI model induced by ␣-naphthylthiourea (ANTU) (30,31), we found that administration of Pentostatin, which elevated lung adenosine level by 10-fold, not only attenuated the development of edema before ALI, but also partially reversed edema after ALI. Our data suggest that both adenosine transporters and A 2A and A 2B receptors are necessary for exerting maximal effect of adenosine on barrier enhancement.…”