Deletion of caveolin-1 protects against oxidative lung injury via up-regulation of heme oxygenase-1 - PubMed (original) (raw)

Deletion of caveolin-1 protects against oxidative lung injury via up-regulation of heme oxygenase-1

Yang Jin et al. Am J Respir Cell Mol Biol. 2008 Aug.

Abstract

Acute lung injury (ALI) is a major cause of morbidity and mortality in critically ill patients. Hyperoxia causes lung injury in animals and humans, and is an established model of ALI. Caveolin-1, a major constituent of caveolae, regulates numerous biological processes, including cell death and proliferation. Here we demonstrate that caveolin-1-null mice (cav-1(-/-)) were resistant to hyperoxia-induced death and lung injury. Cav-1(-/-) mice sustained reduced lung injury after hyperoxia as determined by protein levels in bronchoalveolar lavage fluid and histologic analysis. Furthermore, cav-1(-/-) fibroblasts and endothelial cells and cav-1 knockdown epithelial cells resisted hyperoxia-induced cell death in vitro. Basal and inducible expression of the stress protein heme oxygenase-1 (HO-1) were markedly elevated in lung tissue or fibroblasts from cav-1(-/-) mice. Hyperoxia induced the physical interaction between cav-1 and HO-1 in fibroblasts assessed by co-immunoprecipitation studies, which resulted in attenuation of HO activity. Inhibition of HO activity with tin protoporphyrin-IX abolished the survival benefits of cav-1(-/-) cells and cav-1(-/-) mice exposed to hyperoxia. The cav-1(-/-) mice displayed elevated phospho-p38 mitogen-activated protein kinase (MAPK) and p38beta expression in lung tissue/cells under basal conditions and during hyperoxia. Treatment with SB202190, an inhibitor of p38 MAPK, decreased hyperoxia-inducible HO-1 expression in wild-type and cav-1(-/-) fibroblasts. Taken together, our data demonstrated that cav-1 deletion protects against hyperoxia-induced lung injury, involving in part the modulation of the HO-1-cav-1 interaction, and the enhanced induction of HO-1 through a p38 MAPK-mediated pathway. These studies identify caveolin-1 as a novel component involved in hyperoxia-induced lung injury.

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Figures

**Figure 1.

Deletion of caveolin-1 (cav-1) protected against hyperoxia in vitro. Various cell types were exposed to hyperoxia for 72 hours, and cell viability was measured using CellTiter-Glo Luminescent Cell Viability Assay. (A) Fibroblasts were isolated from wild-type and _cav-1_−/− mice. (B) Endothelial cells were isolated from wild-type and _cav-1_−/− mice. (C) Beas-2B cells were transfected with control siRNA or cav-1 siRNA. Shaded bars: wild-type cells or Beas2B cells transfected with control siRNA; open bars: _cav-1_−/− cells; striped bar: cells transfected with cav-1 siRNA. Insets in A and B: Western blot confirming genotype of fibroblasts and endothelial cells. Inset in C: Western blot analysis indicating the efficacy of cav-1 “knock down” in Beas-2B cells. Similar results were found in at least three independent experiments and one representative figure was shown here. Student's _t-_tests were used to determine statistical significance, and the statistical significance was defined as P < 0.05. Furthermore, cell viability was measured using trypan blue exclusion assays. (D) The same fibroblasts from experiment in A were used. (E) Beas-2B cells were transfected with control siRNA or cav-1 siRNA as described above in C. Shaded bars: wild-type cells or Beas2B cells transfected with control siRNA; open bar: _cav-1_−/− cells; striped bar: cells transfected with cav-1 siRNA. All figures represented at least three independent experiments. (F) Gain-of-function experiment. Wild-type fibroblasts were infected with _ad-cav-1_and ad-lacZ as described in M

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. After 24 hours of hyperoxia, cell viability was measured. Shaded bar: cells infected with ad-lacZ; open bar: cells infected with ad-cav-1. Inset: Western blot analysis indicating the overexpressing cav-1 in wild-type fibroblasts infected with ad-cav-1. Figures represented at least three independent experiments. In each experiment, each point had triplicate samples. *Statistically significant (P < 0.05, Student's t test).

**Figure 1.

Deletion of caveolin-1 (cav-1) protected against hyperoxia in vitro. Various cell types were exposed to hyperoxia for 72 hours, and cell viability was measured using CellTiter-Glo Luminescent Cell Viability Assay. (A) Fibroblasts were isolated from wild-type and _cav-1_−/− mice. (B) Endothelial cells were isolated from wild-type and _cav-1_−/− mice. (C) Beas-2B cells were transfected with control siRNA or cav-1 siRNA. Shaded bars: wild-type cells or Beas2B cells transfected with control siRNA; open bars: _cav-1_−/− cells; striped bar: cells transfected with cav-1 siRNA. Insets in A and B: Western blot confirming genotype of fibroblasts and endothelial cells. Inset in C: Western blot analysis indicating the efficacy of cav-1 “knock down” in Beas-2B cells. Similar results were found in at least three independent experiments and one representative figure was shown here. Student's _t-_tests were used to determine statistical significance, and the statistical significance was defined as P < 0.05. Furthermore, cell viability was measured using trypan blue exclusion assays. (D) The same fibroblasts from experiment in A were used. (E) Beas-2B cells were transfected with control siRNA or cav-1 siRNA as described above in C. Shaded bars: wild-type cells or Beas2B cells transfected with control siRNA; open bar: _cav-1_−/− cells; striped bar: cells transfected with cav-1 siRNA. All figures represented at least three independent experiments. (F) Gain-of-function experiment. Wild-type fibroblasts were infected with _ad-cav-1_and ad-lacZ as described in M

aterials and

M

ethods

. After 24 hours of hyperoxia, cell viability was measured. Shaded bar: cells infected with ad-lacZ; open bar: cells infected with ad-cav-1. Inset: Western blot analysis indicating the overexpressing cav-1 in wild-type fibroblasts infected with ad-cav-1. Figures represented at least three independent experiments. In each experiment, each point had triplicate samples. *Statistically significant (P < 0.05, Student's t test).

**Figure 1.

Deletion of caveolin-1 (cav-1) protected against hyperoxia in vitro. Various cell types were exposed to hyperoxia for 72 hours, and cell viability was measured using CellTiter-Glo Luminescent Cell Viability Assay. (A) Fibroblasts were isolated from wild-type and _cav-1_−/− mice. (B) Endothelial cells were isolated from wild-type and _cav-1_−/− mice. (C) Beas-2B cells were transfected with control siRNA or cav-1 siRNA. Shaded bars: wild-type cells or Beas2B cells transfected with control siRNA; open bars: _cav-1_−/− cells; striped bar: cells transfected with cav-1 siRNA. Insets in A and B: Western blot confirming genotype of fibroblasts and endothelial cells. Inset in C: Western blot analysis indicating the efficacy of cav-1 “knock down” in Beas-2B cells. Similar results were found in at least three independent experiments and one representative figure was shown here. Student's _t-_tests were used to determine statistical significance, and the statistical significance was defined as P < 0.05. Furthermore, cell viability was measured using trypan blue exclusion assays. (D) The same fibroblasts from experiment in A were used. (E) Beas-2B cells were transfected with control siRNA or cav-1 siRNA as described above in C. Shaded bars: wild-type cells or Beas2B cells transfected with control siRNA; open bar: _cav-1_−/− cells; striped bar: cells transfected with cav-1 siRNA. All figures represented at least three independent experiments. (F) Gain-of-function experiment. Wild-type fibroblasts were infected with _ad-cav-1_and ad-lacZ as described in M

aterials and

M

ethods

. After 24 hours of hyperoxia, cell viability was measured. Shaded bar: cells infected with ad-lacZ; open bar: cells infected with ad-cav-1. Inset: Western blot analysis indicating the overexpressing cav-1 in wild-type fibroblasts infected with ad-cav-1. Figures represented at least three independent experiments. In each experiment, each point had triplicate samples. *Statistically significant (P < 0.05, Student's t test).

**Figure 2.

Deletion of cav-1 protected against hyperoxia in vivo. (A) Immunofluorescence and Western blot analysis were performed to evaluate the expression of cav-1 in lung tissue from wild-type and _cav-1_−/− mice. Red stain indicates cav-1. (B) Survival of mice after continuous hyperoxia treatment. _X_-axis: days after hyperoxia; _y_-axis: percentage of survived mice. Solid line: wild-type mice; dotted line: cav-1_−/− mice (n = 22; 11 wild-type mice and 11 cav-1_−/− mice exposed to hyperoxia). The ages of cav-1−/− mice and wild-type mice were between 8 and 12 weeks. In each experiment, we matched the age of wild-type mice and cav-1−/− mice. The difference of ages between the wild-type mice and cav-1−/− mice was 2 days. All wild-type mice died before 120 hours (5 d), no exclusions. *Statistically significant (*P < 0.05; Chi-square test).

**Figure 3.

Deletion of cav-1 reduced lung injury after hyperoxia. (A) Mice were exposed to hyperoxia for 96 hours. Bronchoalveolar lavage fluid was obtained from wild-type and hyperoxia-treated mice, and protein concentration was determined. Shaded bars: mice treated with room air; open bars: mice treated with hyperoxia. *P < 0.05. Four mice in each group were used. Student's t tests were used. Statistical significance was defined as P < 0.05. (B) Lung cellular morphology was examined by transition electronic microscopy (TEM). Upper panels: mice treated with room air. Lower panels: mice exposed to hyperoxia. Left panels: wild-type mice. Right panels: _cav-1_−/− mice. Black arrows: nuclei. Representative figures are shown.

**Figure 3.

Deletion of cav-1 reduced lung injury after hyperoxia. (A) Mice were exposed to hyperoxia for 96 hours. Bronchoalveolar lavage fluid was obtained from wild-type and hyperoxia-treated mice, and protein concentration was determined. Shaded bars: mice treated with room air; open bars: mice treated with hyperoxia. *P < 0.05. Four mice in each group were used. Student's t tests were used. Statistical significance was defined as P < 0.05. (B) Lung cellular morphology was examined by transition electronic microscopy (TEM). Upper panels: mice treated with room air. Lower panels: mice exposed to hyperoxia. Left panels: wild-type mice. Right panels: _cav-1_−/− mice. Black arrows: nuclei. Representative figures are shown.

**Figure 4.

Expression and regulation of heme oxygenase-1 (HO-1) in wild-type and _cav-1_−/− mice. (A) Wild-type and cav-1−/− mice were subjected to hyperoxia in vivo. After 96 hours, lung tissue was excised, homogenized, and analyzed for HO-1 expression by Western blot analysis. Figures represented three independent experiments. *P < 0.05 (statistical analysis was performed using t tests). (B) Time course of hyperoxia-induced HO-1 expression in wild-type and _cav-1_−/− mice. Wild-type and cav-1−/− mice were subjected to hyperoxia in vivo for different days as indicated. Lung tissue was excised, homogenized, and analyzed for HO-1 expression by Western blot analysis. There were no wild-type mice that survived on Day 5 from which to collect lung tissue for Western blot analysis. Figures represented three independent experiments. *P < 0.05 (statistics performed using t tests on time [day]-matched samples). (C) Wild-type and cav-1−/− fibroblasts were exposed to hyperoxia (95% O2, 5% CO2) in vitro for 0 to 72 hours. HO-1 expression was determined by Western blot analysis. Figures represented three independent experiments. *P < 0.05 (statistics performed using t test on time-matched samples). (D) Wild-type fibroblasts were treated with hyperoxia (72 h). The interaction of HO-1 and cav-1 was detected by immunoprecipitation with HO-1 polyclonal antibodies followed by blotting with cav-1 monoclonal antibodies. Figure represented three independent experiments. (E) HO-1 activity in wild-type (open bars) and cav-1−/− (shaded bars) fibroblasts with and without hyperoxia. Wild-type and cav-1−/− fibroblasts were exposed to hyperoxia (95% O2, 5% CO2) in vitro. After 72 hours, HO-1 activity was measured as described in M

aterials and

M

ethods

. Open bars: wild-type cells; shaded bars: cav-1−/− cells. Figure represents three independent experiments. *P < 0.05 (statistics performed using t tests).

**Figure 4.

Expression and regulation of heme oxygenase-1 (HO-1) in wild-type and _cav-1_−/− mice. (A) Wild-type and cav-1−/− mice were subjected to hyperoxia in vivo. After 96 hours, lung tissue was excised, homogenized, and analyzed for HO-1 expression by Western blot analysis. Figures represented three independent experiments. *P < 0.05 (statistical analysis was performed using t tests). (B) Time course of hyperoxia-induced HO-1 expression in wild-type and _cav-1_−/− mice. Wild-type and cav-1−/− mice were subjected to hyperoxia in vivo for different days as indicated. Lung tissue was excised, homogenized, and analyzed for HO-1 expression by Western blot analysis. There were no wild-type mice that survived on Day 5 from which to collect lung tissue for Western blot analysis. Figures represented three independent experiments. *P < 0.05 (statistics performed using t tests on time [day]-matched samples). (C) Wild-type and cav-1−/− fibroblasts were exposed to hyperoxia (95% O2, 5% CO2) in vitro for 0 to 72 hours. HO-1 expression was determined by Western blot analysis. Figures represented three independent experiments. *P < 0.05 (statistics performed using t test on time-matched samples). (D) Wild-type fibroblasts were treated with hyperoxia (72 h). The interaction of HO-1 and cav-1 was detected by immunoprecipitation with HO-1 polyclonal antibodies followed by blotting with cav-1 monoclonal antibodies. Figure represented three independent experiments. (E) HO-1 activity in wild-type (open bars) and cav-1−/− (shaded bars) fibroblasts with and without hyperoxia. Wild-type and cav-1−/− fibroblasts were exposed to hyperoxia (95% O2, 5% CO2) in vitro. After 72 hours, HO-1 activity was measured as described in M

aterials and

M

ethods

. Open bars: wild-type cells; shaded bars: cav-1−/− cells. Figure represents three independent experiments. *P < 0.05 (statistics performed using t tests).

**Figure 4.

Expression and regulation of heme oxygenase-1 (HO-1) in wild-type and _cav-1_−/− mice. (A) Wild-type and cav-1−/− mice were subjected to hyperoxia in vivo. After 96 hours, lung tissue was excised, homogenized, and analyzed for HO-1 expression by Western blot analysis. Figures represented three independent experiments. *P < 0.05 (statistical analysis was performed using t tests). (B) Time course of hyperoxia-induced HO-1 expression in wild-type and _cav-1_−/− mice. Wild-type and cav-1−/− mice were subjected to hyperoxia in vivo for different days as indicated. Lung tissue was excised, homogenized, and analyzed for HO-1 expression by Western blot analysis. There were no wild-type mice that survived on Day 5 from which to collect lung tissue for Western blot analysis. Figures represented three independent experiments. *P < 0.05 (statistics performed using t tests on time [day]-matched samples). (C) Wild-type and cav-1−/− fibroblasts were exposed to hyperoxia (95% O2, 5% CO2) in vitro for 0 to 72 hours. HO-1 expression was determined by Western blot analysis. Figures represented three independent experiments. *P < 0.05 (statistics performed using t test on time-matched samples). (D) Wild-type fibroblasts were treated with hyperoxia (72 h). The interaction of HO-1 and cav-1 was detected by immunoprecipitation with HO-1 polyclonal antibodies followed by blotting with cav-1 monoclonal antibodies. Figure represented three independent experiments. (E) HO-1 activity in wild-type (open bars) and cav-1−/− (shaded bars) fibroblasts with and without hyperoxia. Wild-type and cav-1−/− fibroblasts were exposed to hyperoxia (95% O2, 5% CO2) in vitro. After 72 hours, HO-1 activity was measured as described in M

aterials and

M

ethods

. Open bars: wild-type cells; shaded bars: cav-1−/− cells. Figure represents three independent experiments. *P < 0.05 (statistics performed using t tests).

**Figure 5.

HO activity is required for hyperoxia resistance in cav-1–deficient cells and mice. (A) Wild-type and cav-1−/− cells were subjected to hyperoxia (95% O2, 5% CO2) after pretreatment with SnPP (20 μM; open bars) or vehicle (DMSO; shaded bars). After 72 hours, cell viability was evaluated as previously described. The percentage of surviving cells after hyperoxia was determined. Shaded bars: cells pre-treated with DMSO; open bars: cells pre-treated with SnPP. Results reflect the mean and standard deviation of three determinations (*P < 0.05). Figure represents three independent experiments. Statistical analysis was performed using t tests. (B) SnPP was administered to wild-type or _cav-1_−/− mice by injection (20 μmol/kg/d, intraperitoneally). PBS with the same volume was used as control. The animals were exposed to room air or hyperoxia (95% O2, 5% N2) and time-dependent survival was determined (n = 7 in each group). *P < 0.05 (statistics performed using chi-square tests [categorical data]).

**Figure 6.

Hyperoxia-inducible HO-1 expression requires p38 mitogen-activated protein kinase (MAPK) in wild-type and _cav-1_−/− mice. (A) Expression of phosphor-p38 (p-p38) in wild-type or _cav-1_−/− mice. Wild-type and _cav-1_−/− mice were exposed to room air (RA) or hyperoxia (95% O2, 5% N2) for 96 hours. Total or phospho-p38 MAPK levels were determined by Western blot analysis of lung tissue homogenates. Figure represents three independent experiments (statistics performed using t tests; *P < 0.05). (B) Wild-type or _cav-1_−/− fibroblasts were pretreated with DMSO or SB202190 (10 μM) and then exposed to hyperoxia (95% O2, 5% CO2) or room air (RA) for 72 hours. HO-1 expression was determined by Western blot analysis. Figure represents three independent experiments (statistics performed using t tests; *P < 0.05). (C) Expression of p38 isoforms in wild-type or _cav-1_−/− fibroblasts. Wild-type and _cav-1_−/− fibroblasts were exposed to room air (RA) or hyperoxia (95% O2, 5% N2) for 24 hours. Western blot analysis was performed to determine the expression of p-38 isoforms. Figures represent three independent experiments (statistics performed using t tests; *P < 0.05).

**Figure 6.

Hyperoxia-inducible HO-1 expression requires p38 mitogen-activated protein kinase (MAPK) in wild-type and _cav-1_−/− mice. (A) Expression of phosphor-p38 (p-p38) in wild-type or _cav-1_−/− mice. Wild-type and _cav-1_−/− mice were exposed to room air (RA) or hyperoxia (95% O2, 5% N2) for 96 hours. Total or phospho-p38 MAPK levels were determined by Western blot analysis of lung tissue homogenates. Figure represents three independent experiments (statistics performed using t tests; *P < 0.05). (B) Wild-type or _cav-1_−/− fibroblasts were pretreated with DMSO or SB202190 (10 μM) and then exposed to hyperoxia (95% O2, 5% CO2) or room air (RA) for 72 hours. HO-1 expression was determined by Western blot analysis. Figure represents three independent experiments (statistics performed using t tests; *P < 0.05). (C) Expression of p38 isoforms in wild-type or _cav-1_−/− fibroblasts. Wild-type and _cav-1_−/− fibroblasts were exposed to room air (RA) or hyperoxia (95% O2, 5% N2) for 24 hours. Western blot analysis was performed to determine the expression of p-38 isoforms. Figures represent three independent experiments (statistics performed using t tests; *P < 0.05).

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