Accelerated ischemia/reperfusion-induced injury in autoimmunity-prone mice

Natural Abs have been implicated in initiating mesenteric ischemia/reperfusion (I/R)-induced tissue injury. Autoantibodies have affinity and self-Ag recognition patterns similar to natural Abs. We considered that autoimmunity-prone mice that express high titers of autoantibodies should have enhanced I/R-induced injury. Five-month-old B6.MRL/lpr mice displayed accelerated and enhanced intestinal I/R-induced damage compared with 2-mo-old B6.MRL/lpr and age-matched C57BL/6 mice. Similarly, older autoimmune mice had accelerated remote organ (lung) damage. Infusion of serum IgG derived from 5-mo-old but not 2-mo-old B6.MRL/lpr into I/R resistant Rag-1-/- mice rendered them susceptible to local and remote organ injury. Injection of monoclonal IgG anti-DNA and anti-histone Abs into Rag-1-/- mice effectively reconstituted tissue injury. These data show that like natural Abs, autoantibodies, such as anti-dsDNA and anti-histone Abs, can instigate I/R injury and suggest that they are involved in the development of tissue damage in patients with systemic lupus erythematosus.     

Attenuation of ischemia/reperfusion-induced intestinal injury by oleo-resin from Copaifera langsdorffii in rats

Copaifera langsdorffii oleo-resin (CLOR) is a reputed herbal medicine used to combat gastrointestinal functional disorders. Our previous studies show that CLOR prevents gastric ulceration and promotes wound healing. This study examined the effects of CLOR on intestinal damage associated with mesenteric ischemia/reperfusion in rat. Wistar albino rats were divided into four groups of six in each. Group 1: Sham operated, Group 2: Vehicle + 45 min of ischemia followed by 60 min reperfusion (I/R), Groups 3 and 4: I/R + CLOR (200 and 400 mg /kg, p.o., respectively). All treatments were given 24 h, 12 h and 2 h before I/R. Animals were sacrificed at the end of reperfusion period and ileal tissue samples were obtained for biochemical analysis. Myeloperoxidase (MPO), an index of polymorphonuclear leukocytes; malondialdehyde (MDA), an end product of lipoperoxidation; catalase (CAT), an antioxidant enzyme; reduced glutathione (GSH), a key antioxidant; and nitrite, a marker of nitric oxide (NO) production were determined in ileum homogenates. The results show that I/R produces a significant increase in MDA content, MPO, and CAT activities with a significant decrease in GSH and an elevation in nitrite production, as compared to sham control. CLOR treatment caused significant attenuations in I/R-associated increases of MPO, MDA and CAT activities and on nitrite level. Besides, CLOR could effectively prevent the I/R-associated depletion of GSH. The data indicate that the oleo-resin has a protective action against I/R-induced intestinal tissue damage, which appeared to be, at least in part, due to an antioxidant and anti-lipid peroxidation mechanism.     

Deterioration of ischemia/reperfusion-induced acute renal failure in SOD1-deficient mice

Reactive oxygen species (ROS) are likely candidates for involvement in ischemia/reperfusion-induced acute renal failure (ARF). In this study, the issue of whether superoxide dismutase (SOD1)-deficiency exacerbates the ischemia/reperfusion-induced ARF was examined. At two weeks after a right nephrectomy of mice, the left renal vessels were clipped to induce renal ischemia and were then released after 45 min. The severe renal damage observed at one day was partially recovered at seven days after the induction of ischemia. SOD1^- / -  mice suffer from severe ARF compared with SOD1^+/ -  and SOD1^+/+ mice. The damage was more evident in aged animals (24-28 week old) than younger ones (10-12 week old). The expression of major antioxidative and redox enzymes, except for CuZnSOD, were substantially unchanged. Thus, the increased ARF in SOD1^- / -  mice appears to be mainly attributable to a deficiency in CuZnSOD. These data support the view that ROS are exacerbating factors in ischemia/reperfusion-induced ARF.     

Nitric oxide decreases lung injury after intestinal ischemia

Terada, Lance S., Nancy N. Mahr, and Eugene D. Jacobson.Nitric oxide decreases lung injury after intestinal ischemia. J. Appl. Physiol. 81(6):2456-2460, 1996.After injury to a primary organ, mediators arereleased into the circulation and may initiate inflammation of remoteorgans. We hypothesized that the local production of nitric oxide (NO)may act to limit the spread of inflammation to secondarily targetedorgans. In anesthetized rats, 30 min of intestinal ischemia followed by2 h of reperfusion (I/R) did not increase lung albumin leak. However,after treatment with N^G-nitro-L-arginine methyl ester(L-NAME), intestinal I/R led to increased lung leak, suggesting a protective effect of endogenous NO.The site of action of NO appeared to be the lung and not the gutbecause 1) after treatment withL-NAME, local delivery of NO tothe lung by inhalation abolished the increase in intestinal I/R-inducedlung leak; 2)L-NAME had no effect onepithelial permeability (⁵¹Cr-labeled EDTA clearance) ofreperfused small bowel; and 3) after treatment with L-NAME, localdelivery of NO to the gut by luminal perfusion did not improveepithelial permeability of reperfused intestines. Furthermore,L-NAME increased, and inhaled NOde- creased, the density of lung neutrophils in rats subjected to intestinal I/R, and treatment with the selectin antagonist fucoidan abolished L-NAME-induced lungleak in rats subjected to intestinal I/R. We conclude thatendogenous lung NO limits secondary lung injury after intestinal I/R bydecreasing pulmonary neutrophil retention.

     

Deterioration of ischemia/reperfusion-induced acute renal failure in SOD1-deficient mice

Reactive oxygen species (ROS) are likely candidates for involvement in ischemia/reperfusion-induced acute renal failure (ARF). In this study, the issue of whether superoxide dismutase (SOD1)-deficiency exacerbates the ischemia/reperfusion-induced ARF was examined. At two weeks after a right nephrectomy of mice, the left renal vessels were clipped to induce renal ischemia and were then released after 45 min. The severe renal damage observed at one day was partially recovered at seven days after the induction of ischemia. SOD1^{? / ?} mice suffer from severe ARF compared with SOD1^{+/ ?} and SOD1^+/+ mice. The damage was more evident in aged animals (24–28 week old) than younger ones (10–12 week old). The expression of major antioxidative and redox enzymes, except for CuZnSOD, were substantially unchanged. Thus, the increased ARF in SOD1^{? / ?} mice appears to be mainly attributable to a deficiency in CuZnSOD. These data support the view that ROS are exacerbating factors in ischemia/reperfusion-induced ARF.     

Retina restored and brain abnormalities ameliorated by single-copy knock-in of human NR2E1 in null mice

Nr2e1 encodes a stem cell fate determinant of the mouse forebrain and retina. Abnormal regulation of this gene results in retinal, brain, and behavioral abnormalities in mice. However, little is known about the functionality of human NR2E1. We investigated this functionality using a novel knock-in humanized-mouse strain carrying a single-copy bacterial artificial chromosome (BAC). We also documented, for the first time, the expression pattern of the human BAC, using an NR2E1-lacZ reporter strain. Unexpectedly, cerebrum and olfactory bulb hypoplasia, hallmarks of the Nr2e1-null phenotype, were not fully corrected in animals harboring one functional copy of human NR2E1. These results correlated with an absence of NR2E1-lacZ reporter expression in the dorsal pallium of embryos and proliferative cells of adult brains. Surprisingly, retinal histology and electroretinograms demonstrated complete correction of the retina-null phenotype. These results correlated with appropriate expression of the NR2E1-lacZ reporter in developing and adult retina. We conclude that the human BAC contained all the elements allowing correction of the mouse-null phenotype in the retina, while missing key regulatory regions important for proper spatiotemporal brain expression. This is the first time a separation of regulatory mechanisms governing NR2E1 has been demonstrated. Furthermore, candidate genomic regions controlling expression in proliferating cells during neurogenesis were identified.     

Protective effect of lung inflation in reperfusion-induced lung microvascular injury

We used the isolated-perfused rat lung model to study the influence of pulmonary ventilation and surfactant instillation on the development of postreperfusion lung microvascular injury. We hypothesized that the state of lung inflation during ischemia contributes to the development of the injury during reperfusion. Pulmonary microvascular injury was assessed by continuously monitoring the wet lung weight and measuring the vessel wall (125)I-labeled albumin ((125)I-albumin) permeability-surface area product (PS). Sprague-Dawley rats (n = 24) were divided into one control group and five experimental groups (n = 4 rats per group). Control lungs were continuously ventilated with 20% O(2) and perfused for 120 min. All lung preparations were ventilated with 20% O(2) before the ischemia period and during the reperfusion period. The various groups differed only in the ventilatory gas mixtures used during the flow cessation: group I, ventilated with 20% O(2); group II, ventilated with 100% N(2); group III, lungs remained collapsed and unventilated; group IV, same as group III but pretreated with surfactant (4 ml/kg) instilled into the airway; and group V, same as group III but saline (4 ml/kg) was instilled into the airway. Control lungs remained isogravimetric with baseline (125)I-albumin PS value of 4.9 +/- 0.3 x 10(-3) ml x min(-1) x g wet lung wt(-1). Lung wet weight in group III increased by 1.45 +/- 0.35 g and albumin PS increased to 17.7 +/- 2.3 x 10(-3), indicating development of vascular injury during the reperfusion period. Lung wet weight and albumin PS did not increase in groups I and II, indicating that ventilation by either 20% O(2) or 100% N(2) prevented vascular injury. Pretreatment of collapsed lungs with surfactant before cessation of flow also prevented the vascular injury, whereas pretreatment with saline vehicle had no effect. These results indicate that the state of lung inflation during ischemia (irrespective of gas mixture used) and supplementation of surfactant prevent reperfusion-induced lung microvascular injury.     

Protective role of vascular endothelial growth factor in endotoxin-induced acute lung injury in mice

Background

Vascular endothelial growth factor (VEGF), a substance that stimulates new blood vessel formation, is an important survival factor for endothelial cells. Although overexpressed VEGF in the lung induces pulmonary edema with increased lung vascular permeability, the role of VEGF in the development of acute lung injury remains to be determined.

Methods

To evaluate the role of VEGF in the pathogenesis of acute lung injury, we first evaluated the effects of exogenous VEGF and VEGF blockade using monoclonal antibody on LPS-induced lung injury in mice. Using the lung specimens, we performed TUNEL staining to detect apoptotic cells and immunostaining to evaluate the expression of apoptosis-associated molecules, including caspase-3, Bax, apoptosis inducing factor (AIF), and cytochrome C. As a parameter of endothelial permeability, we measured the albumin transferred across human pulmonary artery endothelial cell (HPAEC) monolayers cultured on porous filters with various concentrations of VEGF. The effect of VEGF on apoptosis HPAECs was also examined by TUNEL staining and active caspase-3 immunoassay.

Results

Exogenous VEGF significantly decreased LPS-induced extravascular albumin leakage and edema formation. Treatment with anti-VEGF antibody significantly enhanced lung edema formation and neutrophil emigration after intratracheal LPS administration, whereas extravascular albumin leakage was not significantly changed by VEGF blockade. In lung pathology, pretreatment with VEGF significantly decreased the numbers of TUNEL positive cells and those with positive immunostaining of the pro-apoptotic molecules examined. VEGF attenuated the increases in the permeability of the HPAEC monolayer and the apoptosis of HPAECs induced by TNF-α and LPS. In addition, VEGF significantly reduced the levels of TNF-α- and LPS-induced active caspase-3 in HPAEC lysates.

Conclusion

These results suggest that VEGF suppresses the apoptosis induced by inflammatory stimuli and functions as a protective factor against acute lung injury.     

Pathogenic importance of pepsin in ischemia/reperfusion-induced gastric injury

We investigated the role of pepsin in the development of ischemia/reperfusion (I/R)-induced gastric lesions in rats. Under urethane anesthesia, the pylorus was ligated, the celiac artery was clamped, and 1 ml of HCl (50-150 mM) was instilled in the stomach. Then, reperfusion was established 15 min later by removing the clamp, and 2 h later the stomach was assessed for gross mucosal damage. Pepstatin (a specific pepsin inhibitor) or pepsin was given i.g. after the pylorus was ligated while cimetidine, omeprazole, or atropine was given s.c. 30 min before the ligation. I/R produced hemorrhagic gastric injury, with a concomitant increase in the amount of pepsin secreted, and the degree of both these responses was dependent on the concentration of HCl. The formation of lesions by IR in the presence of 100 mM HCl was significantly prevented by atropine or bilateral vagotomy, but neither omeprazole nor cimetidine had any effect. Intragastric administration of pepstatin dose-dependently reduced the severity of the I/R-induced gastric lesions, the effect being significant even at 0.1 mg/kg, while that of pepsin markedly aggravated these lesions. The increased pepsin output during I/R was associated with luminal acid loss and significantly inhibited by bilateral vagotomy or pretreatment with atropine but not cimetidine or omeprazole, while pepstatin significantly inhibited the pepsin activity. In conclusion, we suggest that pepsin plays a pivotal role in the pathogenesis of I/R-induced gastric lesions, and pepsin secretion is increased during I/R, the process being associated with acid back-diffusion and mediated through a vagal-cholinergic pathway.     

Mitochondrial transplantation ameliorates ischemia/reperfusion-induced kidney injury in rat

No real therapeutic modality is currently available for Acute kidney injury (AKI) and if any, they are mainly supportive in nature. Therefore, developing a new therapeutic strategy is crucial. Mitochondrial dysfunction proved to be a key contributor to renal tubular cell death during AKI. Thus, replacement or augmentation of damaged mitochondria could be a proper target in AKI treatment. Here, in an animal model of AKI, we auto-transplanted normal mitochondria isolated from healthy muscle cells to injured kidney cells through injection to renal artery. The mitochondria transplantation prevented renal tubular cell death, restored renal function, ameliorated kidney damage, improved regenerative potential of renal tubules, and decreased ischemia/reperfusion-induced apoptosis. Although further studies including clinical trials are required in this regard, our findings suggest a novel therapeutic strategy for treatment of AKI. Improved quality of life of patients suffering from renal failure and decreased morbidity and mortality rates would be the potential advantages of this therapeutic strategy.     

Polycysteine as a new type of radio-protector ameliorated tissue injury through inhibiting ferroptosis in mice

Amifostine has been the only small molecule radio-protector approved by FDA for decades; however, the serious adverse effects limit its clinical use. To address the toxicity issues and maintain the good potency, a series of modified small polycysteine peptides had been prepared. Among them, compound 5 exhibited the highest radio-protective efficacy, the same as amifostine, but much better safety profile. To confirm the correlation between the radiation-protective efficacy and the DNA binding capability, each of the enantiomers of the polycysteine peptides had been prepared. As a result, the l-configuration compounds had obviously higher efficacy than the corresponding d-configuration enantiomers; among them, compound 5 showed the highest DNA binding capability and radiation-protective efficacy. To our knowledge, this is the first study that has proved their correlations using direct comparison. Further exploration of the mechanism revealed that the ionizing radiation (IR) triggered ferroptosis inhibition by compound 5 could be one of the pathways for the protection effect, which was different from amifostine. In summary, the preliminary result showed that compound 5, a polycysteine as a new type of radio-protector, had been developed with good efficacy and safety profile. Further study of the compound for potential use is ongoing.Subject terms: Drug screening, Drug development     

Hypoxia-inducible factor plays a gut-injurious role in intestinal ischemia reperfusion injury

Gut injury and loss of normal intestinal barrier function are key elements in the paradigm of gut-origin systemic inflammatory response syndrome, acute lung injury, and multiple organ dysfunction syndrome (MODS). As hypoxia-inducible factor (HIF-1) is a critical determinant of the physiological and pathophysiological response to hypoxia and ischemia, we asked whether HIF-1 plays a proximal role in the induction of gut injury and subsequent lung injury. Using partially HIF-1α-deficient mice in an isolated superior mesenteric artery occlusion (SMAO) intestinal ischemia reperfusion (I/R) injury model (45 min SMAO followed by 3 h of reperfusion), we showed a direct relationship between HIF-1 activation and intestinal I/R injury. Specifically, partial HIF-1α deficiency attenuated SMAO-induced increases in intestinal permeability, lipid peroxidation, mucosal caspase-3 activity, and IL-1β mRNA levels. Furthermore, partial HIF-1α deficiency prevented the induction of ileal mucosal inducible nitric oxide synthase (iNOS) protein levels after SMAO and iNOS deficiency ameliorated SMAO-induced villus injury. Resistance to SMAO-induced gut injury was also associated with resistance to lung injury, as reflected by decreased levels of myeloperoxidase, IL-6 and IL-10 in the lungs of HIF-1α(+/-) mice. In contrast, a short duration of SMAO (15 min) followed by 3 h of reperfusion neither induced mucosal HIF-1α protein levels nor caused significant gut and lung injury in wild-type or HIF-1α(+/-) mice. This study indicates that intestinal HIF-1 activation is a proximal regulator of I/R-induced gut mucosal injury and gut-induced lung injury. However, the duration and severity of the gut I/R insult dictate whether HIF-1 plays a gut-protective or deleterious role.     

Ethanol modulates gut ischemia/reperfusion-induced liver injury in rats

Whereas both ethanol and gut ischemia/reperfusion (I/R) are known to alter hepatic microvascular function, little is known about the influence of ethanol consumption on the hepatic microvascular responses to I/R. The objective of this study was to determine whether acute ethanol administration exacerbates the hepatic microvascular dysfunction induced by gut I/R. Rats were exposed to gut ischemia for 30 min followed by reperfusion. Intravital videomicroscopy was used to monitor leukocyte recruitment and the number of nonperfused sinusoids (NPS). Plasma alanine aminotransferase (ALT), tumor necrosis factor-alpha (TNF-alpha), and endotoxin concentrations were monitored. In separate experiments, ethanol was administered 15 min or 24 h before gut ischemia. In control rats, gut I/R increased the number of stationary leukocytes and NPS. It also elevated the plasma ALT, TNF-alpha, and endotoxin with a corresponding increase in intestinal mucosal permeability. Low-dose ethanol consumption 15 min before gut ischemia blunted the gut I/R-induced leukostasis and elevations in plasma TNF-alpha and ALT. However, high-dose ethanol consumption aggravated the gut I/R-induced increases in leukostasis and increases in plasma endotoxin and ALT. When ethanol was administered 24 h before, high-dose ethanol aggravated the gut I/R-induced hepatocellular injury, but low-dose ethanol did not have any effects on it. These results suggest that low-dose ethanol consumption shortly before gut ischemia attenuates the hepatic inflammatory responses, microvascular dysfunction, and hepatocellular injury elicited by gut I/R, whereas high-dose ethanol consumption appears to significantly aggravate these gut I/R-induced responses.     

灵芝子实体-益生菌发酵液对环磷酰胺诱发的肠黏膜损伤及菌群紊乱的调节作用

目的 建立灵芝子实体-益生菌发酵体系,并研究该发酵液对于环磷酰胺诱导的肠黏膜损伤及菌群紊乱的防治作用。 方法 通过吸光度(A值)、多糖含量检测等方法评价嗜酸乳杆菌及短双歧杆菌在灵芝子实体提取液中的生长情况。将混合益生菌菌种与灵芝培养基进行共同发酵,发酵液用于对环磷酰胺诱导的肠黏膜损伤模型小鼠的治疗。 结果 嗜酸乳杆菌、短双歧杆菌均能在灵芝子实体的培养基上生长,且A值及总糖含量均高于对照组。该发酵液对环磷酰胺诱导的肠黏膜损伤模型动物有一定的治疗作用,表现为发酵液干预后由环磷酰胺导致的小鼠体质量降低、结肠组织损伤、炎细胞浸润均有所缓解;并恢复肠道菌群结构,显著增加乳杆菌属丰度,降低肠球菌属和鞘脂单胞菌属丰度。 结论 灵芝子实体-益生菌发酵液可以有效改善环磷酰胺诱导的肠黏膜损伤的症状,其机制可能与调节肠道微生态平衡密切相关。     

Proteasome inhibition attenuates lung injury induced by intestinal ischemia reperfusion in rats

The aim of this study is to investigate the role of proteasome in the pathogenesis of lung injury induced by intestinal ischemia/reperfusion (I/R) by examining the effect of the proteasome inhibitor lactacystin on neutrophil infiltration, intracellular adhesion molecule-1 (ICAM-1) expression and nuclear factor kappa B (NF-κB) activation. Thirty-two Wistar rats were divided into (1) control, (2) intestinal I/R, (3) 0.2 mg/kg lactacystin pretreated, and (4) 0.6 mg/kg lactacystin pretreated groups (n = 8). Injuries in lung and intestine were induced by intestinal I/R, and were characterized by histological edema, hemorrhage and infiltration of inflammatory cells. The results showed a significant increase in serum creatine kinase B (CK-B) and lung water content in intestine and lung injuries. As compared with the control group, the myeloperoxidase (MPO) activity in intestine and lung as well as the serum TNF-α level increased significantly in intestinal I/R group. Simultaneously, expression of ICAM-1 and NF-κB p65 was also observed in the I/R group. Pre-treatment with lactacystin markedly reduced 20S proteasome activity in circulating white blood cells and ameliorated intestine and lung injuries. These results demonstrated that the proteasome participates in the pathogenesis of lung injury induced by intestinal I/R. Lactacystin as a proteasome inhibitor can prevent this kind of injury by decreasing ICAM-1 and TNF-α production via the inhibition of NF-κB activation.     

Splenectomy exacerbates lung injury after ischemic acute kidney injury in mice

Patients with acute kidney injury (AKI) have increased serum proinflammatory cytokines and an increased occurrence of respiratory complications. The aim of the present study was to examine the effect of renal and extrarenal cytokine production on AKI-mediated lung injury in mice. C57Bl/6 mice underwent sham surgery, splenectomy, ischemic AKI, or ischemic AKI with splenectomy and kidney, spleen, and liver cytokine mRNA, serum cytokines, and lung injury were examined. The proinflammatory cytokines IL-6, CXCL1, IL-1β, and TNF-α were increased in the kidney, spleen, and liver within 6 h of ischemic AKI. Since splenic proinflammatory cytokines were increased, we hypothesized that splenectomy would protect against AKI-mediated lung injury. On the contrary, splenectomy with AKI resulted in increased serum IL-6 and worse lung injury as judged by increased lung capillary leak, higher lung myeloperoxidase activity, and higher lung CXCL1 vs. AKI alone. Splenectomy itself was not associated with increased serum IL-6 or lung injury vs. sham. To investigate the mechanism of the increased proinflammatory response, splenic production of the anti-inflammatory cytokine IL-10 was determined and was markedly upregulated. To confirm that splenic IL-10 downregulates the proinflammatory response of AKI, IL-10 was administered to splenectomized mice with AKI, which reduced serum IL-6 and improved lung injury. Our data demonstrate that AKI in the absence of a counter anti-inflammatory response by splenic IL-10 production results in an exuberant proinflammatory response and lung injury.     

高密度脂蛋白减轻小鼠内毒素性急性肺损伤

高密度脂蛋白(high density lipoprotein, HDL)是一种血浆含量丰富的脂蛋白,通常认为它可在体内发挥抗炎作用,能够与内毒素结合而抑制其生物活性.为探讨人HDL对内毒素性急性肺损伤的影响,将昆明小鼠分为假手术对照组、脂多糖(lipopolysaccharide, LPS)组、HDL组和LPS HDL组,腹腔注射LPS(10mg/kg体重)复制内毒素性急性肺损伤模型,于腹腔注射LPS 30min后经尾静脉给予人血浆HDL(70mg/kg体重),6h后结束实验.处死动物前抽取动脉血测定血气变化(PaO2, pH, PaCO2).处死后行支气管肺泡灌洗,计数灌洗液中白细胞(white blood cell, WBC)数量,测定蛋白含量和乳酸脱氢酶(lactate dehydrogenase, LDH)活性,并取肺组织进行病理学观察,测定肺组织湿/干重比值、丙二醛(malondialdehyde, MDA)含量、髓过氧化酶(myeloperoxidase, MPO)活性和肿瘤坏死因子-α(tumor necrosis factor α, TNF-α)含量.结果显示:(1)HDL改善小鼠肺换气功能,显著降低LPS所致的PaO2、pH的降低和PaCO2的增高(P<0.01);(2)HDL显著抑制LPS所致的肺泡灌洗液中WBC数量、总蛋白浓度和LDH活性的增高(P<0.01),降低肺组织湿/干重比值、MPO活性、MDA和TNF-α含量(P<0.05, P<0.01);(3)病理形态学分析及评分显示,HDL治疗组小鼠在出血、肺水肿及肺组织内中性粒细胞浸润的程度均低于LPS所致肺损伤组(P<0.01).结果提示,HDL可减轻小鼠内毒素性急性肺损伤.     

Genetic susceptibility to irritant-induced acute lung injury in mice

Recent studies suggest that genetic variability can influence irritant-induced lung injury and inflammation. To begin identifying genes controlling susceptibility to inhaled irritants, seven inbred mouse strains were continuously exposed to nickel sulfate (NiSO(4)), polytetrafluoroethylene, or ozone (O(3)), and survival time was recorded. The A/J (A) mouse strain was sensitive, the C3H/He (C3) strain was intermediate, and the C57BL/6 (B6) strain was resistant to NiSO(4)-induced acute lung injury. The B6AF(1) offspring were also resistant. The strain sensitivity pattern for NiSO(4) exposure was similar to that of polytetrafluoroethylene or ozone (O(3)). Pulmonary pathology was comparable for A and B6 mice. In the A strain, 15 microg/m(3) of NiSO(4) produced 20% mortality. The strain sensitivity patterns for lavage fluid proteins (B6 > C3 > A) and neutrophils (A >/= B6 > C3) differed from those for acute lung injury. This phenotype discordance suggests that these traits are not causally linked (i.e., controlled by independent arrays of genes). As in acute lung injury, B6C3F(1) offspring exhibited phenotypes (lavage fluid proteins and neutrophils) resembling those of the resistant parental strain. Agreement of acute lung injury strain sensitivity patterns among irritants suggested a common mechanism, possibly oxidative stress, and offspring resistance suggested that sensitivity is inherited as a recessive trait.